Skip to main content

Full text of "Scientific misconduct in breast cancer research : hearings before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, House of Representatives, One Hundred Third Congress, second session, April 13 and June 15, 1994"

See other formats


'        SCIENTinC  MISCONDUCT  IN  BREAST  CANCER 

RESEARCH 

Y  4,  EN  2/3: 103-143  ^~ 

Scientific  llisconduct  in  Breast  Can... 

HEARINGS 

BEFORE  THE 

SUBCOMMITTEE  ON 
OVERSIGHT  AND  INVESTIGATIONS 

OF  THE 

COMMITTEE  ON 

ENERGY  AND  COMMERCE 

HOUSE  OF  REPRESENTATIVES 

ONE  HUNDRED  THIRD  CONGRESS 

SECOND  SESSION 


APRIL  13  and  JUNE  15,  1994 


Serial  No.  103-143 


Printed  for  the  use  of  the  Committee  on  Energy  and  Commerce 


r 

--*  .I-—        ■--  :,  - 


'^^    8  re. 


U.S.  GOVERNMENT  PRINTING  OFFICE 
84-5  lOCC  WASHINGTON  :  1994 

For  sale  by  the  U.S.  Government  Printing  Office 
Superintendent  of  Documents,  Congressional  Sales  Office,  Washington,  DC  20402 
ISBN  0-16-046276-2 


'        SCIENTinC  MISCONDUCT  IN  BREAST  CANCER 

RESEARCH 

Y  4.  EN  2/3: 103-143  ^~ 

Scientific  Hisconduct  in  Breast  Can... 

HEARINGS 

BEFORE  THE 

SUBCOMMITTEE  ON 
OVERSIGHT  AND  INVESTIGATIONS 

OF  THE 

COMMITTEE  ON 

ENERGY  AND  COMMERCE 

HOUSE  OF  REPRESENTATIVES 

ONE  HUNDRED  THIRD  CONGRESS 

SECOND  SESSION 


APRIL  13  and  JUNE  15,  1994 


Serial  No.  103-143 


Printed  for  the  use  of  the  Committee  on  Energy  and  Commerce 


/ 


-  -  4  dy 


4^. 


U.S.  GOVERNMENT  PRINTING  OFFICE 


84-5  lOCC  WASHINGTON  :  1994 


For  sale  by  the  U.S.  Government  Printing  Office 
Superintendent  of  Documents,  Congressional  Sales  Office,  Washington,  DC  20402 
ISBN  0-16-046276-2 


COMMITTEE  ON  ENERGY  AND  COMMERCE 


JOHN  D.  DINGELL,  Michigan,  Chairman 


HENRY  A.  WAXMAN,  CaUfornia 

PHILIP  R.  SHARP,  Indiana 

EDWARD  J.  MARKEY,  Massachusetts 

AL  SWIFT,  Washington 

CARDISS  COLLINS,  IlUnois 

MIKE  SYNAR,  Oklahoma 

W.J.  "BILLY"  TAUZIN,  Louisiana 

RON  WYDEN,  Oregon 

RALPH  M.  HALL,  Texas 

BILL  RICHARDSON,  New  Mexico 

JIM  SLATTERY,  Kansas 

JOHN  BRYANT,  Texas 

RICK  BOUCHER,  Virginia 

JIM  COOPER,  Tennessee 

J.  ROY  ROWLAND,  Georgia 

THOMAS  J.  MANTON,  New  York 

EDOLPHUS  TOWNS,  New  York 

GERRY  E.  STUDDS,  Massachusetts 

RICHARD  H.  LEHMAN,  California 

FRANK  PALLONE,  Jr.,  New  Jersey 

CRAIG  A.  WASHINGTON,  Texas 

LYNN  SCHENK,  California 

SHERROD  BROWN,  Ohio 

MIKE  KREIDLER,  Washington 

MARJORIE  MARGOLIES-MEZVINSKY, 

Pennsylvania 
BLANCHE  M.  LAMBERT,  Arkansas 

Alan  J.  Roth,  Staff  Director  and  Chief  Counsel 

Dennis  B.  Fitzgibbons,  Deputy  Staff  Director 

Margaret  A.  Durbin,  Minority  Chief  Counsel  and  Staff  Director 


CARLOS  J.  MOORHEAD,  CaUfornia 

THOMAS  J.  BLILEY,  Jr.,  Virginia 

JACK  FIELDS,  Texas 

MICHAEL  G.  OXLEY,  Ohio 

MICHAEL  BILIRAKIS,  Florida 

DAN  SCHAEFER,  Colorado 

JOE  BARTON,  Texas 

ALEX  MCMILLAN,  North  Carolina 

J.  DENNIS  HASTERT,  IlUnois 

FRED  UPTON,  Michigan 

CLIFF  STEARNS,  Florida 

BILL  PAXON,  New  York 

PAUL  E.  GILLMOR,  Ohio 

SCOTT  KLUG,  Wisconsin 

GARY  A.  FRANKS,  Connecticut 

JAMES  C.  GREENWOOD,  Pennsylvania 

MICHAEL  D.  CRAPO,  Idaho 


Subcommittee  on  Oversight  and  Investigations 


JOHN  D 

SHERROD  BROWN,  Ohio 

MARJORIE  MARGOLIES-MEZVINSKY, 

Pennsylvania 
HENRY  A.  WAXMAN,  CaUfornia 
CARDISS  COLLINS,  Illinois 
RON  WYDEN,  Oregon 
JOHN  BRYANT,  Texas 

Reid  P.F. 
Peter 


DINGELL,  Michigan,  Chairman 

DAr«I  SCHAEFER,  Colorado 
CARLOS  J.  MOORHEAD,  CaUfornia 
JOE  BARTON,  Texas 
FRED  UPTON,  Michigan 


Stuntz,  Staff  Director  I  Chief  Counsel 
D.H.  Stockton,  Research  Analyst 
Bruce  F.  Chafin,  Special  Assistant 
John  J.  Hambel,  Minority  Counsel 


(II) 


CONTENTS 


Page 

Hearings  held  on: 

April  13,  1994  1 

June  15,  1994 101 

Testimony  of: 

Bivens,  Lyle  W.,  Director,  Office  of  Research  Integrity,  Department  of 
Health  and  Human  Services  51 

Broder,  Samuel,  Director,  National  Cancer  Institute 45,  198 

Chabner,  Bruce,  Director,  Division  of  Cancer  Treatment,  National  Cancer 

Institute  45 

Detre,  Thomas,  senior  vice  chancellor  of  health  sciences.  University  of 
Pittsburgh  134 

Fisher,  Bernard,  former  chairman.  National  Surgical  Adjuvant  Breast 
and  Bowel  Project,  University  of  Pittsburgh  168 

Friedman,  Michael  A.,  Associate  Director,  Cancer  Therapy  Evaluation 

Program,  National  Cancer  Institute 45 

Herberman,  Ronald  B.,  interim  chairman.  National  Surgical  Adjuvant 
Breast  and  Bowel  Project,  University  of  Pittsburgh  138 

Milbauer,  Alan,  vice  president,  external  affairs,  Zeneca  Pharmaceuticals 
Group  107 

O'Connor,  J.  Dennis,  chancellor,  University  of  Pittsburgh  132 

Onex,  Joseph,  counsel  to  Bernard  Fisher,  University  of  Pittsburgh  168 

Patterson,  John,  international  medical  director,  Zeneca  Pharmaceuticals 
Group  107 

Pearson,  Cjrnthia  A.,  program  director,  National  Women's  Health  Net- 
work          20 

Plourde,  Paul,  senior  director,  Clinical  and  Medical  Affairs,  Zeneca  Phar- 
maceuticals Group  107 

Schroeder,  Hon.  Patricia,  a  Representative  in  Congress  from  the  State 
of  Colorado 8 

Sigal,  Jill  Lea,  consultant,  Washington,  DC  28 

Snowe,  Hon.  Olympia,  a  Representative  in  Congress  from  the  State  of 
Maine  10 

Varmus,  Harold,  Director,  National  Institutes  of  Health  43 

Visco,  Fran,  president,  National  Breast  Cancer  Coalition  12 

(III) 


SCIENTIFIC  MISCONDUCT  IN  BREAST 
CANCER  RESEARCH 


WEDNESDAY,  APRIL  13,  1994 

House  of  Representatives 
Committee  on  Energy  and  Commerce, 
Subcommittee  on  Oversight  and  Investigations 

Washington,  DC. 

The  subcommittee  met,  pursuant  to  notice,  at  10:05  a.m.,  in  room 
2123,  Rayburn  House  Office  Building,  Hon.  John  D.  Dingell  (chair- 
man) presiding. 

Mr.  Dingell.  The  subcommittee  will  come  to  order. 

Today  the  subcommittee  will  examine  a  number  of  important  is- 
sues associated  with  serious  falsification  and  fabrication  of  data  in 
some  of  the  Nation's  most  important  clinical  trials  on  the  treat- 
ment and  prevention  of  breast  cancer,  the  National  Surgical  Adju- 
vant Breast  and  Bowel  Project,  NSABP,  led  by  Dr.  Bernard  Fisher 
of  the  University  of  Pittsburgh. 

A  particular  focus  of  this  hearing  is  the  Federal  Government's  re- 
sponse to  these  problems.  This  case  has  major  implications  for 
thousands  of  patients  who  have  participated  in  NSABP  studies  for 
decades,  for  the  American  taxpayers  who  have  funded  NSABP 
studies  in  amounts  in  excess  of  $100  million,  and  for  maintaining 
the  public  trust  in  the  integrity  of  science. 

Regrettably,  this  is  only  the  latest  in  a  series  of  cases  that  the 
subcommittee  has  felt  it  necessary  to  examine.  The  subcommittee's 
involvement  in  examining,  investigating  and  monitoring  the  han- 
dling of  cases  of  scientific  misconduct  dates  back  to  1988  when  the 
subcommittee  held  its  first  hearing  on  the  issue. 

Many  in  the  scientific  community  have  resisted  outside  scrutiny 
and  others  have  sought  to  minimize  the  problem.  But  as  we  see 
today,  scientific  misconduct  is  a  very  real  problem  that  requires  an 
intensive  and  aggressive  response  by  the  scientific  community  itself 
and  by  the  Federal  Government.  The  case  before  us  is  a  vivid  re- 
minder of  how  poor  the  response  of  the  scientific  community  can 
be  and  how  serious  consequences  may  be  when  the  scientific  com- 
munity and  the  Federal  Government  fall  down  on  the  job. 

It  is,  I  think,  without  necessity  that  the  Chair  points  out  that  in- 
volved in  this  matter  is  not  only  the  confidence  of  the  country  in 
science,  the  questions  of  expenditure  of  public  money,  but  the  peace 
of  mind  of  literally  millions  of  women  in  the  United  States  who  feel 
great  concern  about  the  possibility  of  cancer  and  the  consequences 
to  them  of  bad  science. 

Before  we  get  into  the  specifics  of  this  case,  the  Chair  would  like 
to  point  out  that  we  will  hear  today  important  reassurances  for 

(1) 


American  women,  and  we  believe  that  is  good.  According  to  the  Na- 
tional Institutes  of  Health,  the  National  Statistical  Analyses  by  the 
National  Cancer  Institute,  NCI,  contractor  indicate  that  the  major 
findings  of  the  NSABP  lumpectomy/mastectomy  study  remain  valid 
even  without  the  inclusion  of  the  fraudulent  data.  However,  be- 
cause recent  revelations  have  shaken  confidence  in  the  entire 
study,  the  Chair  notes  that  audits  are  both  necessary  and  under 
way  to  confirm  the  validity  of  the  remainder  of  the  data  in  the 
NSABP  database. 

What  this  case  shows,  however,  and  what  should  continue  to  be 
of  concern  to  all  Americans  are  major  problems  in  the  handling  of 
this  matter  by  all  concerned.  Patient  records  were  falsified  and  fab- 
ricated for  over  13  years  before  NSABP's  initial  discovery  in  June 
of  1990  of  data  discrepancies  at  Montreal's  St.  Luc  Hospital.  There 
was  no  follow-up  until  September  1990,  when  Pittsburgh  sent  two 
staffers  to  Montreal,  who  not  only  confirmed  this  discrepancy  but 
identified  a  number  of  others.  In  December  one  of  the  NSABP 
audit  staffers  wrote  a  memorandum  describing  that  on  two  occa- 
sions St.  Luc  had  continued  to  report  follow-up  on  patients  who 
had  been  dead  for  6  to  8  months. 

I  have  had  signatures  on  petitions  which  were  filed  against  me 
by  candidates  of  people  who  were  dead,  but  I  assumed  that  went 
on  in  politics  and  not  in  science. 

At  the  beginning  of  December  1990  Dr.  Fisher  told  Dr.  Poisson, 
who  led  the  questioned  work,  that  he  had  a  data  problem  and  that 
NSABP  was  sending  a  team  to  Montreal  to  investigate.  Despite 
talking  with  the  target  of  the  investigation,  Pittsburgh  and  Dr. 
Fisher  still  had  not  disclosed  the  problem  to  NCI. 

In  February  1991  Pittsburgh  sent  its  audit  report  to  Dr.  Poisson 
at  St.  Luc  at  which  time  he  confessed  to  falsifying  and  fabricating 
records.  About  a  week  later  Pittsburgh  formally  notified  NCI  of  the 
fraud.  Eight  months  had  elapsed  since  NSABP's  discovery  of  the 
fabricated  and  falsified  data.  The  Office  of  Research  Integrity,  ORI, 
of  the  Department  of  Health  and  Human  Services  was  notified  and 
then  began  its  investigation. 

In  May  1991  Dr.  Poisson  admitted  his  fraud  and  was  debarred 
for  life  by  the  U.S.  Food  and  Drug  Administration  from  performing 
research  involving  investigational  drugs. 

On  July  3,  1991,  Dr.  Samuel  Broder,  director  of  NCI,  was  briefed 
on  the  status  of  OKI's  St.  Luc  investigation  in  which  ORI  had 
found  "94  cases  involved  data  falsification  or  fabrications  which  can 
be  solidly  documented." 

Dr.  Broder  concluded  that  the  fraudulent  St.  Luc  data  should  be 
removed,  that  all  previously  reported  studies  should  be  reanalyzed 
and  the  reports  published  on  the  reanalysis  of  the  work. 
Reanalyses  have  dribbled  out  over  time  from  Pittsburgh  to  NCI. 
However,  to  this  date,  some  3  years  later,  no  reanalysis  has  been 
published.  In  fact,  the  New  England  Journal  of  Medicine  has  stated 
that  it  will  not  accept  NSABP's  reanalysis  manuscript  until  the  au- 
dits are  completed. 

In  addition.  Dr.  Broder  concluded  that  no  St.  Luc's  data  should 
be  included  in  any  future  publications.  However,  this  was  sum- 
marily ignored  by  Dr.  Fisher.  Dr.  Fisher  submitted  at  least  13  pa- 


pers  that  contained  fraudulent  St.  Luc  data,  of  which  seven  have 
now  been  published. 

Despite  Dr.  Broder's  call  for  an  immediate  reanalysis,  Pittsburgh 
did  not  present  a  reanalysis  until  March  1992.  This  reanalysis  was 
a  simple  slide  show  for  the  NCI/ORI  staff,  claiming  that  the  origi- 
nally published  conclusions  remained  unchanged  when  the  fraudu- 
lent data  were  removed.  NCI/ORI  accepted  this  account,  and  based 
on  the  assumption  that  the  public  health  was  not  at  risk  for  the 
next  year,  NCI/ORI  insisted  on  a  blackout  of  news  about  the  inves- 
tigation. 

Between  1992  and  1994  NCI  sporadically,  and  only  half- 
heartedly, encouraged  NSABP  to  complete  a  manuscript  reporting 
the  reanalysis,  to  significantly  upgrade  its  audit  procedure,  and  to 
establish  a  data  monitoring  committee.  Pittsburgh  moved  forward 
at  an  equally  halfhearted  pace. 

After  public  disclosure  of  this  debacle,  Pittsburgh  delivered  its 
reanalysis  to  NCI  in  a  matter  of  days.  NCI's  internal  statistician 
had  significant  concerns  about  the  adequacy. 

Recently  NCI  discovered  NSABP  was  nearly  1  year  behind  in 
scheduling  site  visit  audits  and  3  years  behind  in  submitting  site 
visit  reports  to  NCI.  Among  the  audit  reports  that  were  submitted 
there  were  numerous  instances  in  which  significant  discrepancies 
apparently  were  left  without  any  investigation  or  other  follow-up. 

For  example,  during  an  emergency  site  visit  to  Pittsburgh  NCI 
uncovered  a  Pittsburgh  audit  report  dated  September  1993  which 
included  evidence  of  serious  irregularity  at  St.  Mary's,  another 
Montreal  hospital.  Despite  the  repercussions  of  the  St.  Luc's  fraud, 
Pittsburgh  did  not  report  this  new  problem  to  NCI,  apparently 
thereby  contributing  to  the  recent  removal  of  Dr.  Fisher  as  prin- 
cipal investigator.  Last  week  ORI  initiated  a  misconduct  investiga- 
tion of  this  apparently  falsified  data. 

One  of  the  reasons  we  are  here  today  is  that  no  one  followed  the 
direction  of  the  director  of  the  NCI.  Top  NCI  officials  ignored  the 
director's  instructions.  Pittsburgh  ignored  the  directions  of  its  fund- 
ing institution.  In  fact,  top  NCI  officials  have  complained  to  the 
subcommittee  staff  that  they  could  not  even  get  Dr.  Fisher  to  re- 
turn their  phone  calls,  let  alone  to  take  direction  from  NCI. 

This  illustrates  a  central  problem  identified  in  numerous  sub- 
committee investigations  of  scientific  misconduct:  Who  is  in  charge, 
the  NIH,  which  is  the  funding  institution,  or  other  funding  institu- 
tions, or  the  prominent  investigators?  NIH's  capability  and  willing- 
ness to  manage  and  oversee  federally  funded  research  continues  to 
be  a  key  question,  and  millions  of  dollars  are  being  spent  on  this 
kind  of  research. 

A  separate  but  related  matter  to  be  discussed  today  underlines 
the  importance  of  disclosing  and  aggressively  responding  to  prob- 
lems. Dr.  Fisher  and  Pittsburgh  did  not  adequately  investigate 
deaths  involved  in  the  use  of  tamoxifen  in  clinical  trials  under  his 
supervision,  nor  did  they  notify  NCI  and  ICI  in  a  timely  manner. 

Tamoxifen  has  been  widely  used  in  treatment  studies  for  years, 
but  only  in  the  last  2  years  has  tamoxifen  been  given  to  healthy 
women  in  a  prevention  trial.  At  the  time  of  the  initiation  of  this 
study  there  were  concerns  about  side  effects,  particularly  uterine 


and  other  cancers,  but  not  a  single  death  at  this  time  had  been  at- 
tributable to  this  risk. 

However,  on  June  25,  1991,  the  first  tamoxifen-related  uterine 
cancer  death  occurred.  The  death  was  reported  to  Pittsburgh  on 
August  5,  1991,  but  Dr.  Fisher  claims  it  took  him  2  years  to  deter- 
mine the  cause  of  death.  He  told  the  staff  of  this  subcommittee  that 
he  was  unable  to  obtain  the  autopsy  analysis  from  the  hospital  in 
his  study. 

In  fact,  by  October  1993  Dr.  Fisher  was  aware  of  at  least  four 
uterine  cancer  deaths  attributable  to  tamoxifen.  Just  last  Friday 
the  FDA  and  the  manufacturer  warned  doctors  about  the  increased 
risk  associated  with  tamoxifen.  The  company  has  told  the  sub- 
committee staff  that  it  first  learned  of  uterine  cancer  deaths  caused 
by  tamoxifen  when  it  was  informed  by  NCI,  not  Dr.  Fisher,  in  De- 
cember 1993. 

Both  of  these  matters,  the  St.  Luc  false  data  and  the  delay  in  re- 
porting tamoxifen  deaths,  show  that  responsible  audits  and  over- 
sight are  critical  to  the  maintenance  of  trust  and  to  scientific 
progress.  The  challenge  before  us  is  to  make  the  scientific  process 
more  open  and  more  accountable  without  politicizing  it  or  burden- 
ing it. 

In  recent  years  the  Congress  has  attempted  to  augment  the  gov- 
ernment's ability  to  combat  scientific  misconduct.  For  example,  in 
1992  we  passed  the  Generic  Drug  Enforcement  Act,  which  debars 
from  FDA  application-related  work  those  involved  in  falsifying 
drug  testing  data  provided  to  the  FDA.  In  1993  we  passed  the  NIH 
Revitalization  Act,  which  requires  the  development  of  research  in- 
tegrity, policy  and  regulations. 

These  statutes  help,  but  they  do  not  substitute  for  administrative 
vigilance  by  NIH  nor  do  they  substitute  for  awareness  and  action 
by  the  scientific  community,  which  has  the  first  and,  indeed,  the 
principal  responsibility  of  policing  itself,  a  matter  on  which  it  must 
succeed  or  other  measures  will  have  to  be  taken  by  statute  or  by 
other  action  by  the  government. 

The  witnesses  today  include  a  woman  victimized  by  breast  can- 
cer, representatives  of  concerned  women's  health  groups,  and  offi- 
cials from  HHS.  These  include  the  director  of  NIH,  the  director  of 
NCI,  the  director  of  the  Office  of  Research  Integrity.  The  Chair  an- 
nounces with  regret  that  Dr.  Fisher  was  unable  to  testify,  citing 
health  reasons.  ICI/Zeneca,  the  manufacturer  of  tamoxifen,  claimed 
inability  to  provide  witnesses  from  the  United  Kingdom  on  a  week's 
notice.  The  committee  may  be  interested  in  hearing  them  on  per- 
haps greater  notice  or  perhaps  a  more  interesting  hearing  at  a 
later  time. 

We  thank  the  witnesses  for  appearing  before  us  today  and  we 
look  forward  to  their  testimony. 

The  Chair  recognizes  the  distinguished  gentleman  from  Colorado 
for  an  opening  statement. 

Mr.  SCHAEFER.  I  thank  the  Chair.  I  really  appreciate  the  Chair 
holding  this  hearing  this  morning. 

Americans  are  perhaps  the  best  informed  people  inhabiting  the 
earth.  CNN  brings  them  news  24  hours  a  day,  and  the  tele- 
communications industry's  super  highways  transfer  certain  vital 
information  at  the  blink  of  an  eye.  But  when  it  comes  to  making 


medical  decisions,  Americans  rely  on  the  integrity  of  scientific  re- 
search and  the  oversight  functions  of  the  Federal  Government  to 
guarantee  that  the  information  being  received  is  accurate  and  com- 
plete. 

In  this  regard,  the  American  people  have  been  let  down  by  the 
scientific  community  and  representatives  of  the  government.  The 
facts  of  this  case  are  well  known.  You  can't  pick  up  a  magazine  or 
a  newspaper  without  seeing  some  mention  of  the  fraud  that  was 
perpetrated  by  Dr.  Poisson. 

While  it  is  hard  to  believe  that  research  scientists  would  delib- 
erately falsify  data  critical  to  an  important  study,  it  is  even  more 
illogical  that  his  colleagues  in  the  scientific  community  seem  to 
have  looked  the  other  way. 

Perhaps  worst  of  all  is  the  fact  that  the  National  Cancer  Insti- 
tute has  disseminated  incorrect  and  misleading  information  that 
has  resulted  in  millions  of  American  women  wondering  about  the 
honesty  and  the  accuracy  of  American  science. 

Mr.  Chairman,  there  is  blame  enough  to  be  spread  around  here 
and  it  is  important  that  we  identify  the  individuals  and  institutions 
responsible  for  this  disaster  and  take  appropriate  actions  to  assure 
that  it  does  not  happen  again.  More  importantly,  however,  we  must 
seek  to  reassure  the  American  people  about  the  soundness  of  Amer- 
ican science. 

I  understand  that,  despite  press  statements  to  the  contrary,  the 
National  Cancer  Institute  has  still  not  conducted  a  comprehensive 
reanalysis  of  the  study  in  question.  This  is  unacceptable.  Unaccept- 
able. NCI's  tardiness  and  inaction  does  a  disservice  to  the  hard 
working  members  of  the  scientific  community  and  to  the  American 
people  who  are  sponsoring  the  research. 

Mr.  Chairman,  I  want  to  commend  you  for  holding  this  hearing 
and  swiftly  bringing  this  matter  to  everybody's  attention.  American 
women  are  scared,  and  rightfully  so.  That  is  why  it  is  important 
that  we  do  everything  that  we  possibly  can  to  allay  their  fears  and 
restore  their  confidence  in  American  research.  I  particularly  am 
very  pleased  to  see  two  colleagues  of  mine,  Congresswoman  Snowe 
and  Congresswoman  Schroeder,  my  colleague  from  the  State  of  Col- 
orado, here  today.  I  thank  you,  Mr.  Chairman  and  yield  back. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman. 

The  Chair  recognizes  now  the  distinguished  gentleman  from 
California,  chairman  of  the  health  subcommittee,  my  friend,  Mr. 
Waxman. 

Mr.  Waxman.  Thank  you  very  much,  Mr.  Chairman. 

Public  confidence  in  the  research  of  the  National  Institutes  of 
Health  and  particularly  its  National  Cancer  Institute  are  as  impor- 
tant to  scientific  progress  as  the  quality  of  its  scientists  or  the  level 
of  its  funding.  Scientific  misconduct,  however  rare,  cannot  be  toler- 
ated and  the  impact,  particularly  upon  clinical  research,  must  be 
remedied  quickly. 

Responsibility  rests  with  the  scientific  managers  of  the  NIH  to 
be  vigilant  and  alert  to  the  potential  for  fraud  and  the  implications 
for  patient  care.  The  response  to  knowledge  of  the  falsified  data 
from  Canada  was  neither  swift  nor  thorough.  The  consequence  has 
been  understandable  concern  on  the  part  of  breast  cancer  patients 
and  their  families. 


I  am  heartened  that  the  recommendations  of  the  National  Cancer 
Institute  regarding  the  use  of  breast-sparing  procedures  remain  un- 
changed. I  pray  the  NCI's  continuing  audit  of  the  National  Surgical 
Adjuvant  Breast  and  Bowel  Project  database  does  not  reveal  addi- 
tional cases  of  misconduct  and  that  the  stronger  administrative 
safeguards  put  in  place  will  deter  a  repetition  of  this  event.  Our 
mothers,  sisters  and  daughters  deserve  nothing  less. 

Mr.  Chairman,  I  want  to  highlight  an  additional  concern  that  our 
subcommittee  is  reviewing  in  cooperation  with  Senator  Rockefeller 
involving  the  tamoxifen  prevention  trial.  Recent  revelations  regard- 
ing the  risk  of  uterine  cancer  have  resulted  in  stronger,  more  ex- 
plicit labeling  changes  for  tamoxifen. 

I  believe  the  NCI's  decision  to  proceed  with  a  prevention  trial  in- 
volving the  administration  of  a  potentially  toxic  drug  to  otherwise 
healthy  women  raises  serious  ethical  questions.  Hard  questions 
need  to  be  asked  about  the  adequacy  of  the  informed  consent  proc- 
ess. We  need  to  carefully  scrutinize  the  planning  process  used  by 
the  National  Cancer  Institute  in  initiating  this  trial. 

I  look  forward  to  working  with  you  on  this  matter  and  I  com- 
mend you  for  holding  this  hearing. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman. 

The  Chair  recognizes  now  the  gentlewoman  from  Illinois,  Mrs. 
Collins. 

Mrs.  Collins.  Thank  you,  Mr.  Chairman.  As  you  know,  I  have 
been  committed  to  fighting  breast  cancer  by  every  means  available 
to  us  for  many,  many  years.  As  a  matter  of  fact,  I  have  pressed  for 
better  coverage  for  poor  women  by  seeking  to  get  preventive  mam- 
mogram screening  covered  under  Medicare  for  years,  having  au- 
thored the  first  such  legislation  way  back  in  1974.  I  supported  ef- 
forts to  educate  the  public  about  the  prevention  and  early  detection 
through  breast  cancer  awareness  months  and  other  kinds  of  activi- 
ties that  have  gone  on. 

I  have  also  supported  standards  for  quality  mammograms  and 
pressed  for  more  attention  and  funding  for  research  on  women's 
health  issues  as  a  whole. 

As  one  who  has  been  active  on  many  fronts  in  the  war  against 
this  disease,  I  must  say  that  it  is  absolutely  disheartening  to  wit- 
ness this  episode.  It  is  difficult  enough  to  discover  that  researchers 
would  falsify  data  that  would  be  used  in  determining  treatment 
regimens  for  breast  cancer  patients  around  the  world,  but  to  learn 
that  every  effort  and  precaution  was  not  taken  in  rooting  out  the 
fraudulent  data  quickly  and  completely  is  truly  tragic. 

Similarly,  I  am  concerned  that  all  speed  was  not  used  to  inform 
the  women  who  have  breast  cancer  and  who  have  the  most  to  lose 
that  there  was  a  problem  with  this  data.  This  is  an  even  more  trag- 
ic consequence.  These  actions  have  at  the  very  least  eroded  public 
trust  in  the  good  efforts  of  the  breast  cancer  research  community 
to  realize  good  treatments  and  preventions  for  this  very  deadly  dis- 
ease. 

I  am  disappointed  too  that  the  women  have  been  put  through 
this  emotional  wringer  and  outraged  that  some  of  the  scientific 
community  have  insensitively  described  their  anguish  as  "fretting." 


I  sincerely  hope  that  this  hearing  will  help  us  to  uncover  what 
went  wrong  at  NSABP  and  at  other  points  in  the  system  and  to 
determine  what  we  can  do  to  keep  it  from  happening  again. 

While  it  is  clear  that  this  episode  has  had  an  abominable  effect 
on  women  confronting  major  decisions  about  treatment  regimens 
for  breast  cancer,  it  is  equally  clear  that  researchers  in  the  breast 
cancer  research  community  who  have  contributed  significantly  in 
the  past  have  sustained  extensive  damage  to  their  professional  rep- 
utations. I  cannot  help  but  wonder  what  effect  the  moratorium  on 
enrolling  new  participants  in  clinical  trials  is  going  to  have  on  the 
many  other  important  studies  that  were  being  run  by  the  NSABP 
or  the  chilling  impact  this  controversy  has  on  new  scientists  or  doc- 
tors when  they  decide  which  research  areas  they  want  to  study. 

Even  so,  I  understand  the  importance  of  airing  this  issue,  be- 
cause it  is  critically  important,  and  I  think  it  is  the  only  way  that 
we  can  regain  confidence  in  the  important  work  of  the  NSABP  and 
the  other  government  agencies  that  are  involved.  Without  our  over- 
sight, we  could  find  ourselves  in  this  situation  again  and,  worse 
still,  suspect  the  integrity  of  the  scientific  data  on  which  women 
must  make  life  and  death  decisions. 

Mr.  Chairman,  I  am  anxious  to  hear  from  today's  witnesses  and 
hope  that  through  their  testimony  we  can  begin  to  rebuild  some  of 
the  public  trust  in  the  way  the  government  oversees  medical  re- 
search. I  thank  you,  Mr.  Chairman,  and  yield  back  the  balance  of 
my  time. 

Mr.  DiNGELL.  The  Chair  thanks  my  good  friend  from  Illinois  for 
a  very  valuable  opening  statement. 

The  Chair  recognizes  the  gentleman  from  Oklahoma,  Mr.  Synar, 
for  an  opening  statement. 

Mr.  Synar.  Mr.  Chairman,  thank  you  very  much.  I  join  with  my 
colleagues  today  in  discussing  this  very  important  subject.  I  think 
it  is  important  that  we  try  to  relieve  some  of  the  tension  and  the 
emotion  of  this  issue  and,  more  importantly,  to  try  to  present  a 
front  that  we  are  concerned  about  the  research  that  is  going  on. 
Millions  of  women  throughout  this  country  are  counting  on  this 
government  and  this  Congress  to  make  sure  that  this  happens,  and 
I  join  with  you  in  this  hearing. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman  for  a  very  helpful 
opening  statement. 

The  Chair  recognizes  the  gentlewoman  from  Pennsylvania,  Ms. 
Margolies-Mezvinsky. 

Ms.  Margolies-Mezvinsky.  Thank  vou,  Mr.  Chairman.  Mr. 
Chairman,  I  want  to  thank  you  especially  for  holding  this  impor- 
tant hearing  on  behalf  of  all  of  the  women  and  our  families  in  this 
country,  women  faced  with  breast  cancer,  our  daughters  who  may 
face  this  dreaded  disease,  and  all  of  the  families  that  must  confront 
the  painful  decisions  in  treating  this  disease. 

In  my  district  alone,  Montgomery  County,  women  face  one  of  the 
highest  rates  of  breast  cancer  in  the  State  of  Pennsylvania.  Every 
family  that  has  been  sitting  around  at  a  dinner  table  and  has  had 
to  make  the  difficult  decision  about  what  treatment  to  choose  for 
our  loved  ones,  be  it  mother,  daughter  or  wife,  deserves  to  know 
the  truth  and  the  findings  behind  these  government  financed  stud- 
ies. When  that  trust  is  violated,  like  it  was  by  the  National  Cancer 


8 

Institute  and  by  the  National  Surgical  Adjuvant  Breast  and  Bowel 
Project,  women  and  our  families  in  this  country  have  the  right  to 
be  outraged. 

As  important,  we  deserve  answers  as  to  why  our  own  govern- 
ment misled  us.  Women  now  face  even  more  fear  and  greater  un- 
certainty because  of  these  recent  disclosures  that  data  was  falsified 
and  fabricated.  Our  government  must  get  its  house  in  order  and 
must  properly  ensure  the  absolute  validity  of  its  own  studies.  The 
women  of  this  Nation  deserve  better,  and  I  am  eager  to  see  that 
we  get  the  facts  about  the  dangers  that  confront  us  in  order  to 
make  informed  decisions  about  our  lives  in  the  future. 

I  am  particularly  pleased  to  welcome  Ms.  Frances  Visco  from 
Philadelphia,  who  is  president  of  the  National  Breast  Cancer  Coali- 
tion. 

Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentlewoman  from  Penn- 
sylvania. 

The  Chair  advises  that  pursuant  to  the  rules  of  the  committee 
it  is  within  the  discretion  of  the  Chair  to  permit  nonmembers  of  the 
committee  to  make  opening  statements,  so  the  Chair  is  going  to 
now  recognize  the  two  gentlewomen  who  are  most  interested  in 
this  in  the  House,  Ms.  Schroeder  of  Colorado  and  Ms.  Snowe  of 
Maine.  The  Chair  will  recognize  first  the  gentlewoman  from  Colo- 
rado and  then  the  gentlewoman  from  Maine. 

STATEMENT  OF  HON.  PATRICIA  SCHROEDER,  A  REPRESENTA- 
TIVE IN  CONGRESS  FROM  THE  STATE  OF  COLORADO 

Ms.  Schroeder.  Mr.  Chairman,  I  thank  you  for  letting  us  sit  in. 
Congresswoman  Snowe  and  I  are  here  to  thank  you  and  thank  my 
colleague  from  Colorado  and  everyone  on  this  committee  for  calling 
this  hearing.  This  committee  is  really  one  of  the  beacons  of  light 
that  the  women's  caucuses  look  to. 

As  I  think  back,  it  was  about  4  years  ago  we  were  in  this  very 
hearing  room  when  we  first  heard  from  the  Government  Account- 
ing Office  that  one  more  time  NIH  had  not  paid  attention  to  its 
own  guidelines  and  did  not  have  any  women  in  the  research  mod- 
els. We  thank  you  for  your  constant,  constant  diligence  in  this  area. 

But  I  must  say,  here  we  are,  4  years  later,  and  you  wonder  if 
these  researchers  are  ever  going  to  catch  on.  This  is  a  serious  in- 
tegrity issue.  It  is  about  a  disease  that  will  kill  46,000  women  in 
this  country  this  year  and  afflict  another  182,000,  and  yet  some- 
body felt,  ah,  it  wasn't  that  important;  they  could  sit  on  this  fal- 
sified data  and  not  do  anything  with  it,  and,  by  the  way,  it  didn't 
matter  anjrway  because  they  had  some  other  data. 

Is  it  any  wonder  sometimes  we  women  think  that  we  are  not  get- 
ting a  decent  deal  and  that  our  health  is  not  being  treated  with  the 
same  respect  that  other  people's  are? 

I  was  very  pleased  to  hear  Congressman  Waxman's  concerns 
about  tamoxifen.  One  more  time  we  find  out  about  that,  but  there 
was  a  great  delay  from  when  they  knew  to  when  they  did  anything 
about  it,  and  so  I  really  have  great  questions  whether  this  trial 
should  continue.  If  you  lured  some  women  in  who  didn't  sign  the 
consent  decrees  and  they  knew  it  at  that  time  and  now  they  are 


going  to  keep  the  trial  going,  I  think  one  more  time  it  is  saying  we 
are  playing  fast  and  loose  with  women's  health. 

I  think  it  is  time  we  say  to  these  researchers  there  is  only  one 
reason  I  vote  for  money  for  medical  research,  and  that  is  because 
I  think  good  medical  research  is  going  to  come  around  as  good 
treatment;  it  is  not  to  give  them  a  little  sandbox  they  can  play  in 
and  do  anything  they  want  and  not  be  accountable  to  anybody  and 
never  have  to  answer  any  questions. 

Somehow  I  thought  this  was  the  ego  center  of  America,  but  I  am 
beginning  to  think  some  of  the  scientific  ivory  towers  are  the  ego 
center  of  America,  because  they  get  Federal  money  from  those  of 
us  who  give  it  to  them  and  then  they  turn  around  and  are  abso- 
lutely offended  that  we  would  ever  ask  questions  about  the  quality 
of  it.  If  we  can't  get  quality  research  that  leads  to  quality  treat- 
ment, then  why  are  we  even  spending  money  for  it?. 

There  is  absolutely  no  question  that  women  are  beginning  not  to 
trust  anything  the  government  does.  For  4  long  years  this  sub- 
committee, the  women's  caucus  and  many  of  us  have  been  pound- 
ing away  trying  to  get  this  changed,  and  for  4  long  years  it  says 
a  lot  of  people  still  haven't  gotten  the  message. 

Thank  you,  Mr.  Chairman.  I'm  sure  we  are  all  going  to  work  to- 
gether to  find  some  way  we  finally  do  give  them  the  message  or 
shut  off  their  money,  one  or  the  other.  I  thank  you  for  calling  this 
hearing. 

Mr.  DiNGELL.  The  time  of  the  gentlewoman  has  expired. 

[The  prepared  statement  of  Ms.  Schroeder  follows:] 

Statement  of  Hon.  Patricia  Schroeder,  a  Representative  in  Congress  from 

THE  State  of  Colorado 

Mr.  Chairman,  thank  you  for  allowing  me  to  join  you  here  on  the  dias  today,  even 
though  I  am  not  a  member  of  this  subcommittee.  I'm  breaking  away  from  chairing 
a  Research  and  Technology  Subcommittee  hearing,  so  I  hope  you'll  excuse  me  if  I 
give  my  opening  statement  and  run. 

As  co-cnair  of  the  Congressional  Caucus  for  Women's  Issues  and  on  behalf  of 
women  across  the  country,  I  want  to  thank  you  for  taking  women's  health  seriously. 
These  hearings  are  a  benchmark — thev  signify  the  new  standards  of  proof  that 
women  are  demanding  from  research  that  will  ultimately  determine  whether  they 
live  or  die. 

Science  has  to  be  accountable  to  people.  Mr.  Chairman,  because  you  have  been 
so  vigilant  in  being  America's  eyes  and  ears  on  scientific  fraud,  I  applaud  you.  But 
you  can't  do  it  alone.  We  need  people  who  are  consumers  of  this  information  to  have 
a  role  in  how  science  is  done. 

The  concept  of  "checks  and  beilances"  must  extend  to  science.  Women's  experience 
with  the  scientific  research  community  is  proof  of  this.  It  was  right  here  in  this  com- 
mittee room  4  years  ago  that  the  General  Accounting  Office  released  its  report  say- 
ing that  the  National  Institutes  of  Health  was  not  enforcing  its  own  policy  of  includ- 
ing women  in  clinical  trials. 

That  revelation  led  to  a  revolution  in  women's  health  research.  I  believe  that  your 
work  here  today  on  the  recent  fraud  in  breast  cancer  research  and  the  flaws  in  how 
scientific  research  is  conducted  in  this  country  will  lead  to  another  revolution — one 
in  which  consumers  are  part  of  the  decision-making  process  of  how  science  is  as- 
sessed. 

Consumers  are  not  scientists.  We  know  that.  But  we  are  not  stupid,  either.  We 
don't  want  lies  or  sugar-coated  results — -just  information,  good  information.  We  do 
not  want  to  be  patronized,  especially  in  issues  of  life  and  death. 

Let  me  turn  to  the  specifics  of  this  hearing.  The  National  Surgical  Adjuvant 
Breast  and  Bowel  Project  was  looking  into  the  survival  rates  of  women  with  breast 
cancer  who  had  lumpectomies  or  mastectomies.  The  project's  1985  study  said 
mastectomies  usually  weren't  necessary,  which  meant  many  women  were  saved 
from  the  disfigurement  and  trauma  of  having  their  entire  breasts  removed. 


10 

And  then  we  found  out  that  a  Montreal  doctor  had  falsified  some  data  in  the 
study,  devastating  the  women  who  had  undergone  or  were  considering  surgery,  and 
casting  a  shadow  over  what  little  research  there  was  on  women's  health.  As  if  this 
werent  enough,  we  learned  that  the  head  of  the  project,  Dr.  Bernard  Fisher,  was 
aware  of  this  fraud  since  1990  and  that  the  National  Cancer  Institute  knew  about 
it  since  1991.  So,  all  this  time  passed  without  a  published  reevaluation  of  the  find- 
ings. 

This  is  serious  business,  Mr.  Chairman.  We're  talking  about  women's  lives.  We're 
talking  about  the  integrity  of  the  science  behind  treatment  of  a  disease  that  will 
kill  46,000  women  this  year  and  afflict  another  182,000.  We're  talking  about  re- 
search with  a  conscience. 

We're  told  the  fraudulent  data  didn't  affect  the  results  of  this  and  other  studies. 
Even  if  that  is  true,  it  is  unforgivable  that  women's  health  and  well-being  should 
have  been  treated  so  cavalierly,  or  that  women  should  have  been  so  needlessly 
frightened. 

None  of  this  has  been  helped  by  the  recent  developments  with  tamoxifen,  a  drug 
used  to  treat  breast  cancer.  Once  again  we  encounter  the  National  Surgical  Adju- 
vant Breast  and  Bowel  Project,  Dr.  Bernard  Fisher,  the  NCI,  and  delays  in  inform- 
ing women  about  risks.  And  those  risks,  as  we  recently  have  learned,  involve  higher 
incidences  of  uterine  and  other  cancers,  and  a  possible  link  between  the  drug  and 
a  DES-like  syndrome  in  fetuses.  There  have  even  been  some  deaths. 

The  NCI  and  the  National  Surgical  Adjuvant  Breast  and  Bowel  Project  knew 
about  this  updated  data  last  fall.  But  that  data  didn't  get  incorporated  into  the  in- 
formed consent  document  for  the  prevention  trial,  which  involves  healthy  women 
with  no  history  of  breast  cancer,  until  mid-January  of  this  year.  There  are  still  some 
women  participating  in  this  trial  who  have  not  been  informed  of  these  risks.  It's 
questionable  wnether  the  trial  should  even  continue. 

The  bottom  line  in  all  of  this  is  that  quality  of  research  translates  into  quality 
of  treatment — and  the  trust  that  people  place  in  that  treatment.  And  women  have 
very  little  trust  right  now  because  their  research  has  been  compromised,  resulting 
in  too  many  confusing  signals. 

Your  role  in  uncovering  scientific  fraud  and  insisting  science  be  accountable  is 
critical.  Giving  consumers  a  role  as  well  would  help  restore  women's  trust  in  the 
research  they  have  funded  with  their  tax  dollars.  And  I  think  it  would  help  save 
lives. 

Mr.  DiNGELL.  The  Chair  recognizes  the  gentlewoman  from 
Maine,  Ms.  Snowe. 

STATEMENT  OF  HON.  OLYMPIA  J.  SNOWE,  A  REPRESENTATIVE 
IN  CONGRESS  FROM  THE  STATE  OF  MAINE 

Ms.  Snowe.  Thank  vou,  Mr.  Chairman.  I  want  to  join  Congress- 
woman  Schroeder  in  thanking  you  and  Mr.  Schaefer  for  inviting  us 
to  sit  on  the  subcommittee  today  to  discuss  this  very  important 
issue  to  millions  of  American  women,  and  I  want  to  thank  you  for 
your  timeliness  in  investigating  this  issue  and  the  circumstances 
surrounding  breast  cancer  fraud  in  the  research. 

I  have  to  say,  as  Congresswoman  Schroeder  said,  we  have  been 
dealing  with  many  lapses  in  women's  health  issues.  We  dealt  with 
a  lapse  in  funding,  a  lapse  in  enforcement  policy  that  led  to  the 
systematic  exclusion  and  discrimination  against  women  in  clinical 
study  trials,  and  now  we  are  dealing  with  an  ethics  lapse,  a  very 
serious  lapse  in  a  long  string  of  lapses  concerning  women's  health 
matters. 

I  have  to  say  that  it  just  shatters  our  confidence  in  the  medical 
and  the  scientific  establishment  and  clearly  undermines  our  trust 
in  our  ability  to  conduct  accurate  and  fair  clinical  study  trials,  and 
it  strikes  at  the  very  heart  of  women's  fears  as  to  whether  or  not 
the  clinical  study  trial  process  which  is  the  basis  upon  which  we 
get  information  about  breast  cancer,  has  now  been  jeopardized. 

We  spend  billions  of  dollars.  That  is  what  we  have  been  trying 
to  do  as  the  Congresswomen's  Caucus,  to  increase  the  amount  of 


11 

funding  for  breast  cancer,  and  we  have  done  that.  We  established 
an  Office  of  Women's  Health  Research  at  NIH.  We  galvanized 
women  all  across  America  to  be  educated  and  aware  of  the  need 
to  have  mammograms,  and  the  medical  community,  and  we  have 
done  that.  Now  we  find  out  that  we  cannot  entrust  our  health  re- 
searchers with  accurate  information  and  reliable  data.  It  truly  is 
disheartening. 

I  think  women  in  America,  at  least  in  the  response  that  we  have 
had  as  the  Congresswomen's  Caucus  to  the  efforts  to  upgrade  wom- 
en's health  funding  and  put  it  on  a  level  playing  field,  finally  saw 
the  light  at  the  end  of  the  tunnel,  that  their  needs  were  finally 
being  addressed  and  not  ignored.  Well,  that  light  at  the  end  of  the 
tunnel  has  sort  of  been  snuffed  out  by  this  most  recent  disclosure. 

More  disheartening  than  the  fact  that  the  falsified  data  was  in- 
cluded in  published  studies  is  the  way  in  which  this  issue  has  been 
handled  by  our  primary  research  institute.  As  has  been  mentioned, 
it  was  discovered  in  June  of  1990,  but  it  took  8  months  before  a 
report  was  made  by  any  project  official.  It  took  8  months.  And  it 
has  been  3  years  since  Dr.  Poisson  had  admitted  the  fraud  in  the 
first  place  and  4  years  since  the  discovery  of  the  initial  discrepancy. 
Four  years.  And  it  was  just  1  month  ago  that  the  American  public 
discovered  this  information. 

Why  did  it  take  so  long  to  inform  the  public?  Why  has  it  taken 
so  long  for  the  National  Cancer  Institute  to  reanalyze  this  informa- 
tion when  in  fact  they  made  a  request  for  reanalysis  in  June  1992 
and  January  1993?  In  fact,  in  October  of  1992  NCI  apparently  ad- 
monished the  project  staff  of  their  audit  policy,  noting  that  prob- 
lems with  the  St.  Luc  data  went  undetected  for  13  years  and  that 
the  project's  audit  policy  contributed  to  the  delay  in  detecting  sig- 
nificant data  irregularities. 

The  real  terrifying  impact  of  this  research  fiasco  ultimately  is  on 
the  victims,  those  women  who  have  breast  cancer,  because  they  are 
going  to  be  haunted  by  the  notion  as  to  whether  or  not  they  have 
made  a  correct  decision;  they  are  going  to  question  the  data,  the 
accuracy  of  the  scientific  inwrmation,  their  doctor's  recommenda- 
tion. And  who  can  blame  them,  Mr.  Chairman?  How  can  we  allay 
their  fears  given  this  real  atrophy  of  our  institutions'  medical  re- 
search abilities,  and  who  can  really  blame  them  for  doubting  what 
decisions  they  have  made? 

In  1992,  according  to  Newsweek  magazine,  45,000  women  chose 
to  have  lumpectomies  and  117,000  chose  to  have  mastectomies.  It 
seems  to  me  that  these  women  deserve  to  know  the  truthful  an- 
swers with  respect  to  the  choices  that  they  have  made.  The  women 
of  America  deserve  no  less. 

Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentlewoman. 

The  Chair  advises  that  we  will  now  qualify  our  first  panel.  Our 
first  panel  is  composed  of  Ms.  Cynthia  A.  Pearson,  program  direc- 
tor. National  Women's  Health  Network;  Ms.  Frances  Visco,  presi- 
dent. National  Breast  Cancer  Coalition;  and  Ms.  Jill  Sigal. 

Ladies,  if  you  will  please  come  forward.  The  Chair  would  like  to 
welcome  each  of  you  for  your  presence  today  and  your  assistance 
to  us.  It  is  much  appreciated  and  we  believe  that  your  assistance 
will  enable  us  to  have  not  only  a  better  record,  but  to  move  vigor- 


12 

ously  forward  to  correct  the  concerns  that  I  know  you  share  with 
us  today. 

As  you  know,  it  is  the  practice  of  the  committee  that  all  wit- 
nesses testify  under  oath.  Do  any  of  you  have  any  objection  to  testi- 
fying under  oath? 

[No  response.] 

Mr.  DiNGELL.  The  Chair  advises  in  addition  to  this  that  it  is  your 
right  to  be  advised  by  counsel  if  you  testify  under  oath.  Do  any  of 
you  desire  to  be  advised  by  counsel  during  your  appearances  here? 

[No  response.] 

Mr.  DiNGELL.  The  Chair  advises  also  that  copies  of  the  rules  in 
conformity  with  the  Rules  of  the  House,  the  Rules  of  the  Sub- 
committee, the  Rules  of  the  Full  Committee,  the  Rules  of  the  House 
are  there  in  the  red  and  blue  books  available  to  you  to  inform  you 
of  your  rights  as  you  appear  here  and  also  of  the  limitations  on  the 
powers  of  the  committee. 

Ladies,  if  you  have  no  objection  to  testifying  under  oath,  if  you 
would  please  each  rise  and  raise  your  right  hand. 

[Witnesses  sworn.] 

Mr.  DiNGELL.  You  may  each  consider  yourself  under  oath.  The 
committee  will  recognize  you  in  this  order.  First,  Ms.  Visco;  second, 
Ms.  Pearson;  and  third,  Ms.  Sigal.  Again,  the  Chair  thanks  you  for 
your  assistance  and  cooperation  with  the  committee. 

TESTIMONY  OF  FRAN  VISCO,  PRESIDENT,  NATIONAL  BREAST 
CANCER  COALITION;  CYNTHIA  A-  PEARSON,  PROGRAM  DI- 
RECTOR, NATIONAL  WOMEN'S  HEALTH  NETWORK;  AND  JILL 
LEA  SIGAL,  CONSULTANT,  WASHINGTON,  DC. 

Ms.  VisCO.  Thank  you,  Mr.  Chairman  and  members  of  the  En- 
ergy and  Commerce  Subcommittee  on  Oversight  and  Investiga- 
tions. I  am  Fran  Visco.  I'm  a  breast  cancer  survivor,  I'm  a  wife  and 
mother,  and  the  president  of  the  National  Breast  Cancer  Coalition. 
I  was  diagnosed  with  breast  cancer  in  1987  and  I  chose  to  have  a 
lumpectomy  rather  than  a  mastectomy  based  on  my  own  independ- 
ent readings  and  the  information  and  advice  given  to  me  by  physi- 
cians. 

On  behalf  of  the  National  Breast  Cancer  Coalition  and  the  2.6 
million  women  who  are  living  with  breast  cancer  in  this  country 
today,  I  want  to  thank  you  for  your  work  on  breast  cancer  and  for 
this  hearing  today.  It  is  an  extremely  important  happening. 

A  diagnosis  of  breast  cancer  carries  with  it  a  never-ending  sense 
of  unease,  of  concern  and  fear.  Because  of  my  own  diagnosis  and 
my  work  with  the  National  Breast  Cancer  Coalition,  my  life  is  peo- 
pled with  women  who  have  heard  the  words,  'Tou  have  breast  can- 
cer", with  their  families  and  friends.  We  are  everyone.  We  are  law- 
yers, we  are  scientists,  we  are  Members  of  Congress,  we  are  teach- 
ers, homemakers,  mothers  and  daughters.  We  are,  by  and  large,  a 
medically  sophisticated  vocal  group  who  live  day  in  and  day  out 
with  the  threat,  the  fear  and  the  pain  of  breast  cancer. 

About  3  years  ago  many  of  us  took  that  fear  and  we  turned  out- 
ward into  a  national  advocacy  movement,  and  we  formed  the  Na- 
tional Breast  Cancer  Coalition.  Our  mission  is  to  eradicate  the 
breast  cancer  epidemic.  Our  goals  are  to  increase  research  and 
funding,  to  ensure  access  for  all  women,  and  to  increase  the  influ- 


13 

ence  of  women  with  breast  cancer  and  other  consumer  advocates  in 
the  decision-making  that  impacts  our  lives. 

Recently  the  anxiety  and  fear  with  which  we  live  daily  has  been 
exacerbated  by  a  barrage  of  events.  First,  the  unfortunate  manner 
in  which  the  National  Cancer  Institute  announced  its  decision  to 
change  the  guidelines  for  mammography;  then  the  news  belatedly 
announced  fraud  in  the  lumpectomy  studies;  and  finally,  the  uter- 
ine cancer  deaths  from  tamoxifen. 

No  one  at  the  National  Breast  Cancer  Coalition  has  been  un- 
touched by  these  recent  events  at  NCI  and  NSABP.  Mr.  Chairman, 
we  must  do  more  to  ensure  that  these  systems  that  allow  this 
fraud  to  occur,  that  allow  the  information  to  be  kept  from  the  pub- 
lic, are  held  responsible  and  corrected. 

While  we  appreciate  the  fact  that  it  appears  as  though  this  time 
women's  health  in  general  and  women  with  breast  cancer  in  par- 
ticular were  not  placed  in  great  jeopardy  by  the  deceit  and  neg- 
ligence of  the  scientists  involved,  we  are  outraged  that  the  informa- 
tion was  kept  from  the  public,  from  women  with  breast  cancer, 
from  women  who  had  decisions  to  make,  and  from  other  scientists 
and  other  scientific  institutions,  from  the  physicians  who  were  ad- 
vising women. 

With  a  diagnosis  of  breast  cancer  we  find  ourselves  in  a  world 
over  which  we  have  very  little  control.  We  have  to  learn  a  new  sci- 
entific language.  And  we  do.  We  have  to  understand  new  concepts. 
And  we  do.  And  we  are  asked  to  turn  ourselves  over  unthinking, 
unquestioning  to  the  scientific  and  medical  communities.  We  do 
not.  Not  any  longer.  We  insist  on  being  part  of  the  decision-making 
that  impacts  our  lives. 

The  recent  barrage  of  news  about  breast  cancer  research  and 
treatment  underscores  the  urgency  and  necessity  of  our  demand 
that  consumer  advocates,  that  breast  cancer  advocates  have  a  seat 
at  the  table. 

The  discovery  that  officials  at  NCI  and  NSABP  not  only  knew 
about  the  fraud  but  that  they  did  nothing  to  make  this  important 
information  readily  available  to  the  public  and  the  scientific  com- 
munities is  the  most  disturbing  fact.  This  failure  to  respond  has 
caused  advocates  to  question  the  level  of  trust  that  the  public 
places  in  these  institutions.  After  the  dust  has  cleared  from  all  the 
media  attention,  the  congressional  inquiries  there  will  still  remain 
a  crisis  of  confidence  among  millions  of  women  who  have  been 
asked  to  trust  the  institutions  charged  with  acting  in  the  best  in- 
terest of  our  health. 

I  recognize  that  Dr.  Bernard  Fisher  was  a  visionary  in  the  field 
of  breast  cancer  and  that  his  leadership  in  the  area  was  in  part  re- 
sponsible for  the  advances  that  have  been  made  in  this  disease, 
and  I  also  recognize  the  tensions  and  difficulties  faced  by  the  Na- 
tional Institutes  of  Health  and  the  National  Cancer  Institute. 

I  have  received  a  number  of  telephone  calls  over  the  past  weeks 
from  members  of  the  scientific  community.  They  want  to  make  cer- 
tain that  we  activists  understand  that  we  must  not,  in  their  words, 
"Throw  the  baby  out  with  the  bath  water",  that  we  must  not  insist 
on  controls  that  are  so  severe  that  the  scientific  process  is  unneces- 
sarily impeded.  We  know.  We  understand.  But  we  still  must  ask 
these  questions.  What  procedures  were  followed?  Did  they  conform 


14 

with  accepted  standards?  And  if  they  did,  are  the  accepted  stand- 
ards sufficient?  And  most  critically,  if  the  status  quo  is  such  that 
scientific  fraud  is  kept  from  the  public,  from  other  scientists  and 
from  our  physicians,  then  the  status  quo  must  change. 

We  understand  the  need  for  large  clinical  trials.  We  support 
them;  we  advocate  for  them;  but  we  need  change.  In  this  situation 
nothing  changed.  This  information  has  been  available  for  quite 
sometime  but  nothing  changed  until  activists  and  advocates  spoke 
out,  until  the  Congressional  Caucus  for  Women's  Issues  spoke  out, 
until  you,  Mr.  Chairman,  and  this  committee  spoke  out  and  held 
these  hearings. 

We  know  we  must  be  clear  for  American  women.  There  are  other 
studies  that  support  the  results  of  the  NSABP  studies.  There  are 
benefits  to  tamoxifen.  And  if  we  have  all  of  the  information  we 
need,  we  can  make  informed  decisions. 

I  have  been  told  not  to  overreact,  not  to  question  too  much.  We 
didn't  perform  fraud.  We  didn't  neglect  to  uncover  fraud  for  13 
years.  We  didn't  delay  reanalysis  of  data.  We  didn't  keep  informa- 
tion from  the  public.  The  scientific  community  did  that,  and  we 
have  every  right  and  indeed  a  responsibility  to  call  them  to  task 
for  this.  I'm  sitting  here.  I'm  a  member  of  the  President's  Cancer 
Panel;  I'm  a  breast  cancer  survivor;  I  lead  a  national  breast  cancer 
organization;  and  I  found  out  about  this  by  picking  up  the  New 
York  Times.  And  I  still  don't  know  what  happened,  what  was 
reanalyzed,  when  it  was,  who  did  it,  who  is  involved. 

The  public  trust  in  the  system  is  eroding  and  we  are  going  to  get 
it  back  through  hearings  like  this  and  by  letting  consumers  be  part 
of  the  decision-making  process. 

This  sorry  story  reveals  a  system  overly  concerned  with  profes- 
sional reputation  and  institutional  ego,  both  public  and  private  in- 
stitutional ego.  And  while  the  participants  shuffle  to  position  them- 
selves to  best  protect  themselves  and  to  point  a  finger  at  someone 
else,  I  ask  them  to  stop  and  to  look  at  me,  look  at  all  the  women 
in  this  room,  all  the  women  in  your  lives.  It  is  my  life;  it  is  our 
lives  that  your  decisions  impact.  It  is  my  money;  it  is  public  money 
that  you  spend.  We  women  with  breast  cancer,  consumer  advocates 
belong  at  the  table.  We  must  be  a  part  of  the  decision-making,  of 
data  monitoring  committees,  of  oversight  committees,  of  study  sec- 
tions. 

There  is  resistance  in  the  scientific  community  to  this.  We  want 
to  "micromanage  their  research."  We  "don't  understand."  "Science 
is  pure."  But  we  are  here  spending  much  time  and  money  to  fix  im- 
pure science  and  bad  decisions.  Science  is  not  a  concept  that  exists 
in  a  vacuum.  It  is  performed  too  often  in  isolation,  insulated  from 
the  public  by  individuals,  by  imperfect  people  with  biases  and 
shortcomings.  That  is  why  we  need  a  strong  system  of  checks  and 
balances,  oversight,  different  perspectives  that  will  allow  science  to 
proceed  unimpeded  by  ego,  fraud  and  erosion  of  public  trust,  and 
that  will  occur  if  consumer  advocates  are  given  an  informed,  mean- 
ingful seat  at  the  table. 

I  recently  read  in  the  paper  a  quote  from  a  top  official  of  NCI 
who  said  if  a  year  or  two  ago  he  had  been  able  to  intuit  women's 
concerns  about  the  NCI  and  NSABP  behavior,  NCI  would  have 
acted  differently.  Well,  there  is  a  fundamental  deficiency  in  a  sys- 


15 

tern  where  a  public  servant  believes  he  must  intuit  how  the  public 
must  react  to  decisions  made  by  his  agency.  Had  a  consumer  advo- 
cate, a  woman  with  breast  cancer  been  part  of  the  process  the 
public's  peace  of  mind  and  women's  lives  would  not  have  been  left 
to  the  uncertainties  of  an  individual's  intuitive  ability.  This  self-im- 
posed separation  between  public  agencies  and  the  public  they  serve 
is  unacceptable. 

We  are  gathered  here  today  because  of  a  crisis,  a  fundamentsd 
flaw  in  the  systems  that  are  supposed  to  protect  us.  I  feel  very 
strongly,  and  I  know  you  share  that,  that  we  would  do  a  larger  dis- 
service to  the  women  of  this  country  if  we  did  not  use  this  as  an 
opportunity  to  ensure  this  does  not  happen  again.  Let's  make  it  a 
matter  of  policy  that  consumers,  breast  cancer  advocates  are  in- 
volved at  every  stage  of  the  research  process,  from  advisory  boards 
to  study  sections  at  the  agency  level,  to  steering  committees,  data 
monitoring  committees  and  IRB's  at  the  institutional  and  study 
levels.  We  have  to  be  a  part  of  this. 

I  want  to  thank  you,  Mr.  Chairman  and  members  of  this  sub- 
committee. Your  work  has  brought  us  closer  to  reestablishing  pub- 
lic confidence  in  our  institutions  and  the  scientific  process,  but  I 
know  that  I  do  not  want  this  to  be  the  method  of  oversight  of 
science. 

Thank  you. 

Mr.  DiNGELL.  Ms.  Visco,  thank  you  for  your  very  helpful  testi- 
mony. We  appreciate  your  presence  and  your  assistance. 

Ms.  Pearson. 

[The  prepared  statement  and  attachment  of  Ms.  Visco  follow:] 


16 


1^1  National 
r^^  Breast  C: 


_  Cancer 

±  Z  Coalition 

a  grassroots  advocacy  effort 


PO  Box  663"'} 
Washington.  DC  20035 

(202)  296-7477  Testimony  of  Fran  Visco 

President,  National  Breast  Cancer  Coalition 

before  the 

Subcommittee  on  Oversight  and  Investigations 

April  13,  1994 


Thank  you,  Uli.  Chairman  and  members  of  the  Energy  and  Commerce 
Subcommittee  on  Oversight  and  Investigations.   I  am  Fran  Visco,  a  breast  cancer 
survivor,  a  wife  and  mother,  a  lawyer  and  President  of  the  National  Breast  Cancer 
Coalition. 

On  behalf  of  the  National  Breast  Cancer  Coalition  and  the  2.6  million  women 
who  are  now  living  with  breast  cancer,  thank  you  for  your  work  on  the  pressing  issues  of 
breast  cancer  and  for  the  opportunity  to  testify  before  this  Subcommittee. 

A  diagnosis  of  breast  cancer  carries  with  it  a  never-ending  sense  of  unease,  of 
fear,  of  concern.   Because  of  my  own  diagnosis  and  my  work  with  the  National  Breast 
Cancer  Coalition,  my  life  is  now  peopled  with  women  who  have  heard  the  words,  "you 
have  breast  cancer",  with  their  families  and  friends,  with  women  and  men  who  have  lost 
loved  ones  to  this  disease.   We  are  everyone  -  we  are  lawyers,  scientists,  Members  of 
Congress,  teachers,  bomemakers,  mothers  and  daughters.   We  are,  by  and  large,  a 
sophisticated,  vocal  group  who  live  day  in  and  day  out  with  the  threat,  the  fear  and  the 
pain  of  breast  cancer. 

About  three  years  ago,  many  of  us  took  that  fear  and  turned  it  outward,  into  a 
national  advocacy  movement  -  the  National  Breast  Cancer  Coalitioa  The  Coalition  is  a 
grassroots  advocacy  organization  dedicated  to  the  eradication  of  the  breast  cancer 
epidemic.   We  are  made  up  of  more  than  270  organizations  and  thousands  of  individual 
women,  their  families,  friends  and  health  care  providers. 

Our  mission  is  to  eradicate  the  breast  cancer  epidemic.  Our  goals  are  to  increase 
funding  for  breast  cancer  research  and  to  help  focus  the  research  on  prevention  and 
cure,  as  well  as  treatment  and  screenings;  to  ensure  access  for  all  women  to  health  care 
and  to  increase  the  influence  of  women  living  with  breast  cancer  and  other  breast  cancer 
advocates  in  the  decision  making  that  impacts  their  lives. 


17 


Recently  the  anxiety  and  fear,  with  which  we  live  daily  has  been  escalated  by  a 
barrage  of  events:   first,  the  unfortunate  manner  in  which  the  National  Cancer  Institute 
announced  its  decision  to  change  the  guidelines  for  mammography  screening;  then,  the 
news,  (belatedly  announced),  of  fraud  in  the  lumpectomy  studies;  and  finally,  the  uterine 
cancer  deaths  from  the  tamoxifen  trials. 

No  one  at  NBCC  has  been  untouched  by  the  recent  events  at  NCI  and  the 
National  Surgical  Adjuvant  Breast  and  Bowel  Project.   Mr.  Chairman,  we  must  do  more 
to  ensure  that  the  systems  that  allowed  this  fraud  to  occur  are  held  responsible  and 
corrected.   We  are  very  disturbed  to  learn  the  extent  of  the  fraud.   While  we  appreciate 
the  fact  that  it  appears  as  though  this  time  women's  health  in  general,  and  women  with 
breast  cancer  in  particular,  were  not  placed  in  great  jeopardy  by  the  deceit  and 
negligence  of  the  scientists  involved,  we  are  outraged  that  the  information  was  kept  from 
the  public,  from  other  institutions,  and  from  health  care  providers. 

With  the  diagnosis  of  breast  cancer,  we  find  ourselves  in  a  world  over  which  we 
have  little  control.   We  must  learn  a  new  scientific  language  -  we  do;  we  must 
understand  new  concepts  -  we  do;  we  are  asked  to  turn  ourselves  over,  unthinking  and 
unquestioning,  to  the  scientific  and  medical  communities  -  we  do  not,  not  any  longer.  I 
know  that  many  members  of  the  scientific  community  -  and  most  of  those  in  power  -  do 
not  believe  that  we  belong  at  the  table.  They  tell  us  their  science  is  "pure"  and  that  our 
involvement  will  somehow  interfere  with  their  work.  They  accuse  us  of  wanting  to 
"micromanage"  research.  The  scientific  community  does  not  understand:   it  is  not  our 
intent  to  micromanage  what  they  do  or  to  interfere  with  the  process  of  research.  We 
have  simply  learned  that  when  the  process  is  left  solely  to  the  scientists,  women  are  not 
well  served.  The  recent  barrage  of  bad  news  about  breast  cancer  research  and  treatment 
underscores  the  urgency  and  necessity  of  our  demand  that  breast  cancer  advocates, 
including  women  with  breast  cancer,  have  a  seat  at  the  table. 

We  are  here  today  because,  time  after  time,  it  is  unclear  whether  women's  health 
is  truly  at  the  center  of  concern.  Certainly  Doctor  Roger  Poisson's  fraud  is  indefensible. 
What  really  concerns  me  though,  is  how  we  deal  with  these  problems  when  they  arise. 

The  discovery  that  officials  at  the  National  Cancer  Institute  and  the  National 
Surgical  Adjuvant  Breast  and  Bowel  Project  not  only  knew  about  the  fraud,  but  that  they 
did  nothing  to  make  this  important  information  readily  available  to  the  public  is  the  most 
disturbing  faa.  This  failure  to  respond  to  the  breach  of  scientifically  valid  research 
techniques  has  caused  breast  cancer  advocates  to  question  the  level  of  trust  which  the 
public  places  in  these  institutions.  After  the  dust  has  cleared  from  all  of  the  media 
attention  and  congressional  inquiries,  there  will  remain  a  crisis  of  confidence  among 
millions  of  women  who  have  been  asked  to  trust  the  institutions  charged  with  acting  in 
the  best  interest  of  our  health. 

The  lumpectomy  study  at  NSABP  is  an  enormous  undertaking  --  it  involves 
hundreds  of  international  sites.  Granted,  as  the  size  of  any  study  increases,  it  becomes 
more  and  more  difficult  to  exercise  absolutely  tight  controls.   But  the  problem  in  this 


18 


case  is  that  when  it  became  clear  -  years  ago  --  that  the  data  from  this  landmark  study 
were  false,  nothing  was  done  to  ensure  that  women's  health  was  protected.   Opportunity 
after  opportunity  to  correct  the  false  data  were  lost.   It  is  hard  to  believe  that  there  was 
ever  any  real  intent  to  ensure  that  women  and  their  doctors  were  aware  of  the  problems 
in  the  study.   It  frightens  me  to  think  when,  or  if,  we  would  have  ever  learned  the  truth  if 
the  Chicago  Tribune  hadn't  done  its  own  research. 

Unfortunately,  the  lumpectomy  studies  aren't  the  only  thing  imder  scrutiny  today. 
The  Food  and  Drug  Administration  released  information  last  Friday  about  the  dangers 
of  the  drug  tamoxifen  which  has  been  used  successfully  in  women  after  surgery  for  breast 
cancer.  Unfortunately,  tamoxifen  has  also  been  shown  to  increase  the  risk  of  uterine 
cancer.  Six  women  who  were  taking  tamoxifen  to  prevent  the  recurrence  of  disease  are 
dead  of  uterine  cancer.  Currently,  healthy  women  are  enrolled  in  tamoxifen  trials  to 
determine  if  it  is  an  effective  preventive  agent  for  breast  cancer.  Thousands  of  women 
are  still  enrolled  in  this  trial  at  unknown  risk  to  their  lives.   I  am  concerned  that  once 
again,  efforts  will  not  be  made  to  inform  the  public  about  the  risks  associated  with  this 
drug.   When  NCI  develops  and  tests  a  drug  successfully,  there  is  a  large  publicity  effort, 
but  when  studies  show  unexpected  risks,  somehow  that  information  gets  bogged  down  in 
procedure  and  protocols.  Consumers  -  women  with  breast  cancer  -  are  the  last  to 
know. 

Mr.  Chairman,  we  must  ensure  that  women  are  informed  in  a  timely  manner 
about  the  risks  they  assume  when  participating  in  any  kind  of  scientific  study. 
Presumably,  lumpectomy  studies  and  tamoxifen  trials  are  undertaken  in  the  best  interests 
of  women  and  their  health.   But  as  research  goes  forward,  the  best  interests  of  women 
become  secondary  to  scientific  protocol,  to  bureaucracy,  and  to  preservation  of 
professional  reputations. 

I  have  received  several  messages  over  the  past  week  from  members  of  the 
scientific  community.  The  scientists  want  to  make  certain  that  I  understand  that  we 
should  not,  in  their  words,  "throw  the  baby  out  with  the  bath  water";  that  we  must  not 
insist  on  controls  that  are  so  severe  that  the  scientific  process  is  unnecessarily  impeded. 
We  know.   We  know.   But  we  still  must  ask  these  questions:   What  procedures  were 
followed?   Did  they  conform  with  the  accepted  standards?  And  if  they  did,  are  the 
accepted  standards  sufficient?   Most  critically,  if  the  status  quo  is  such  that  scientific 
fraud  is  kept  from  the  public,  from  other  scientists,  from  our  physicians,  then  the  status 
quo  must  change. 

I  recognize  that  Dr.  Bernard  Fisher  was  a  visionary  in  the  field  of  breast  cancer. 
And  that  his  leadership  in  this  area  was  in  part  responsible  for  the  advances  that  have 
been  made.   I  also  recognize  the  tensions  and  difficulties  faced  by  the  National  Institutes 
of  Health  and  the  National  Cancer  Institute.   But  when  we  concentrate  too  much  power 
in  too  few  people,  we  do  a  disservice  to  the  public.   I  have  seen  what  individual, 
professional,  and  institutional  ego  can  do:   those  in  power  get  to  a  point  where  they 
become  insulated  from  the  public  and  from  the  patients  they  serve. 

We  are  gathered  here  today  because  of  a  crisis  -  a  fundamental  flaw  in  the 
systems  that  are  supposed  to  protect  us.     But  I  feel  very  strongly  that  we  would  do  a 
larger  disservice  to  women  if  we  do  not  use  this  as  an  opportunity  to  ensure  justice  in  the 
future.   We  must  make  it  a  matter  of  policy  that  consumers  -  breast  cancer  advocates  - 
are  involved  at  every  stage  of  the  research  process,  from  advisory  boards  to  study 
sections  at  the  agency  level,  to  steering  committees;  data  monitoring  committees  and 
IRB's,  at  the  institutional  and  study  level.   Women  must  be  a  part  of  the  research 
process  if  their  best  interests  are  to  be  fully  ensured. 

Thank  you  Mr.  Chairman  and  members  of  the  Subcommittee. 


19 


(i^B  National 
r-^^  Breast  Cancer 
•  ^*  Coalition 

^T   Al^l  a  grassroots  advocacy  effort 

NATIONAL  BREAST  CANCER  COALITION  STATEMENT 
P  o  Box  66373  jj^  RESPONSE  TO  NSABP  DATA  FALSIFICATION 

Wuhingioa.  DC  2003  S 

(202)  296-7477 

A  tenet  of  the  National  Breast  Cancer  Coalition  policy  agenda  is  that  consumers  -  breast 
cancer  advocates  -  belong  at  every  level  of  the  research  process,  from  advisory  boards  to 
study  sections  at  the  agency  level,  to  steering  committees,  data  monitoring  committees  and  IRBs,  at 
the  instinitional  and  study  level.   To  advance  this  agenda," for  the  past  three  years,  the  Coalition  has 
met  with  top  officials  at  the  National  Institutes  of  Health  and  the  National  Cancer  Institute,  and 
demanded  meaningful  representation  at  every  level. 

Recent  events  at  the  National  Cancer  Institute  and  the  National  Surgical  Adjuvant  Breast  and 
Bowel  Project  (NSABP)  underscore  the  necessity  of  including  consumer  advocates  at  the  table.   NCI 
and  NSABP  knew  for  several  years  of  falsification  of  data  that  were  used  in  critical  breast  cancer 
smdies  of  the  efficacy  of  lumpectomy  for  certain  breast  cancers  and  the  efficacy  of  tamoxifen  in 
preventing  recurrence  and  death  from  breast  cancer,  and  failed  to  reveal  this  information  to  the 
public.    In  fact,  a  manuscript  submitted  by  NSABP  to  the  NCI  journal  in  January,  1994  included 
results  from  an  investigator  known  to  have  fabricated  data. 

In  response  to  the  public's  outcry  that  information  has  been  kept  from  it,  a  top  official  of 
NCI  recently  was  quoted  as  saying  that  if  a  year  or  two  ago  he  had  "intuited"  women's  concerns  to 
the  NCI/NSABP  behavior,  NCI  would  have  acted  differently.  There  is  a  fundamental  deficiency  in  a 
system  where  a  public  servant  believes  he  must  intuit  how  the  public  may  react  to  decisions  made  by 
his  agency.  Had  a  consumer  advocate  -  a  woman  with  breast  cancer  -  been  pan  of  the  process,  the 
public's  peace  of  mind  and  women's  lives  would  not  have  been  left  to  the  uncertainties  of  an 
individual's  intuitive  abilities.   This  self-imposed  separation  between  the  public  agencies  and  the 
citizenry  they  serve  is  unacceptable.  ^^^     ' 

The  behavior  of  the  NCI  and  the  NSABP  have  put  women's  lives  at  risk.   These  recent 
revelations  have  undermined  the  effectiveness  of  the  NCI  and  NSABP  and  have  caused  breast  cancer 
advocates  to  question  the  level  of  trust  to  which  these  institutions  are  entitled  from  the  public. 

The  public  funds  biomedical  research;  scientists  who  perform  this  research  are  accountable  to 
the  public.    NCI  and  NSABP's  failure  to  disclose  these  data  in  a  timely  manner  impinges  upon  the 
rights  of  the  patient  who  is  entitled  to  make  her  decisions  with  all  relevant  information  revealed,  of 
the  scientist  and  physician  who  have  a  responsibility  to  the  process  and  their  patients,  and  of  the 
public  that  funds  the  research. 

The  vast  amounts  of  money  spent  on  biomedical  research  warrant  structures  that  do  not 
consolidate  power  in  the  few,  but  rather  foster  diversification.    Diversification  will  result  in  new 
ideas  and  approaches  and  decreased  opportunities  for  development  of  a  "club-like"  atmosphere 
among  researchers.   This  will  help  to  build  a  system  of  checks  and  balances  and  minimize  the 
possibility  of  vital  information  being  kept  from  the  public. 

The  National  Breast  Cancer  Coalition  demands  an  independent  investigation  of  both  the 
underlying  falsification  of  the  data  submitted  to  the  NSABP  and  of  the  failure  of  NCI  and  the 
NSABP  to  timely  disclose  information  to  the  public.   We  demand  that  the  names  of  the 
biostatisticians  named  as  investigators  by  the  NCI  be  revealed  immediately  and  that  the  nature  of 
their  charge  be  made  public  at  once. 


20 

TESTIMONY  OF  CYNTHIA  A-  PEARSON 

Ms.  Pearson.  Good  morning,  Chairman  Dingell,  members  of  the 
committee.  Thank  you  for  inviting  us  to  participate  in  this  impor- 
tant hearing.  I  represent  the  National  Women's  Health  Network. 
The  Network  is  a  strong  supporter  of  clinical  trial  research  for 
women.  We  remember  all  too  vividly  the  harm  that  women  suffered 
when  they  were  treated  on  the  basis  of  hope  or  belief  rather  than 
scientific  knowledge. 

When  we  have  a  context  of  that  kind  of  commitment  to  clinical 
trial  research,  we  were  shocked  to  find  out  that  those  involved  in 
conducting  and  overseeing  breast  cancer  treatment  trials  have 
withheld  information  about  falsified  data.  We  were  angry  when  we 
learned  from  the  press  that  the  National  Cancer  Institute  and 
NSABP  delayed  for  over  1  year  after  a  final  report  from  ORI  docu- 
menting falsified  data  in  NSABP.  We  were  angry  when  we  learned 
that  no  reanalysis  had  been  done.  In  the  past  NCI  has  rushed 
NSABP's  results  to  the  public  when  there  was  good  news.  To  delay 
announcing  falsification  of  data  within  breast  cancer  trials  makes 
it  appear  tnat  Dr.  Fisher  and  NCI  want  the  public  to  know  results 
only  if  they  reflect  well  on  NSABP  and  NCI. 

This  disregard  for  the  public's  right  to  know  is  outrageous.  We 
commend  Congress  for  stepping  in  when  it  appears  that  NCI  isn't 
able  to  assert  its  authority.  Dr.  Fisher  was  seemingly  unable  or  un- 
willing to  follow  NSABP's  own  guidelines  for  auditing  of  data  and 
timely  reporting  of  possible  problems.  NCI  apparently  took  none  of 
the  appropriate  measures  that  would  have  ensured  compliance. 

Dr.  Fisher's  failure  to  report  problems  with  data  in  the  breast 
cancer  treatment  trials  and  NCI's  failure  to  require  compliance  ap- 

Eear  to  be  paralleled  by  their  actions  with  regard  to  the  tamoxifen 
reast  cancer  prevention  trial.  In  this  prevention  trial  important 
information  that  volunteers  and  the  general  public  need  to  know  is 
withheld  for  unreasonably  long  periods  of  time,  and  when  eventu- 
ally given  to  women,  it  is  incomplete  and  misleading. 

By  withholding  information  about  the  effects  of  the  drug  used  in 
the  prevention  trial,  NCI  and  Dr.  Fisher  are  attempting  to  sidestep 
a  public  discussion  of  the  wisdom  of  continuing  this  trial. 

The  breast  cancer  prevention  trial,  originally  a  bad  idea,  is  well 
on  its  way  to  becoming  a  disaster.  The  trial  was  a  bad  idea  to  begin 
with  because  it  wasn't  designed  to  prevent  disease — breast  can- 
cer— in  healthy  women.  Because  it  is  using  a  drug — ^tamoxifen — 
that  is  known  to  have  serious  side  effects,  it's  an  attempt  to  sub- 
stitute one  disease  for  another.  And  now,  because  of  the  recent  rev- 
elations, we  find  that  the  risks  of  tamoxifen  are  actually  much 
worse. 

We  believe  that  if  these  results  which  have  been  withheld  were 
openly  disclosed  when  the  trial  began  that  it  would  not  have  been 
approved.  We  also  believe  that  the  new  information  is  enough  jus- 
tification to  stop  the  trial.  To  let  this  trial  proceed  is  to  watch 
women  die  of  trust. 

We  would  like  to  briefly  review  for  you  the  chronology  of  misin- 
formation by  omission  and  commission  in  which  Dr.  Fisher  and 
NCI  have  collaborated. 

In  April  1992,  when  the  trial  began,  healthy  volunteers  were 
given  a  consent  form  that  was  misleading  in  two  very  important 


21 

ways.  It  told  them  the  risk  of  an  increased  chance  of  uterine  cancer 
was  about  three.  That  risk  was  based  on  old  data,  which  Dr.  Fisher 
and  NCI  well  knew  more  cases  had  been  reported.  It  also  told 
women,  "No  deaths  from  uterine  cancer  were  reported." 

In  fact,  as  you  said  in  your  introduction,  as  early  as  1991  Dr. 
Fisher  and  NSABP  knew  that  a  tamoxifen  treated  breast  cancer 
patient  who  developed  uterine  cancer  had  died,  but  instead  of 
warning  women  of  this  possible  risk,  the  consent  form  told  women 
that  uterine  cancers  that  had  occurred  were  thought  to  be  curable. 

After  the  trial  began.  Congress  attempted  to  exercise  some  over- 
sight. Congressman  Ted  Weiss  chaired  the  Human  Resources  and 
Intergovernmental  Relations  Subcommittee.  They  held  an  inquiry 
and  a  hearing  later  in  1992.  NIH,  led  by  that  time  by  Dr.  Healy, 
resisted  all  efforts  for  that  committee  to  exercise  its  oversight  into 
the  quality  of  consent  that  was  taking  place  at  the  trial  and  into 
the  scientific  basis  for  conducting  the  trial.  The  trial  continued  as 
planned. 

Throughout  1992  and  1993  reports  of  different  kinds  of  problems, 
new  kinds  of  problems  with  tamoxifen  emerged  and  were  reported 
in  the  scientific  literature.  These  reports  described  liver  damage, 
eye  problems,  skyrocketing  estrogen  levels  in  pre-menopausal 
women,  cancers  of  the  gastrointestinal  tract,  and  aggressive 
endometrial  cancers. 

Through  1992  and  1993  NCI  and  Dr.  Fisher  were  strangely  si- 
lent about  the  results  of  the  important  large  tamoxifen  breast  can- 
cer treatment  trial  called  B-14.  That  trial  had  reported  in  1991 
originally  no  uterine  cancers  associated  with  treating  breast  cancer 
patients  with  tamoxifen.  Well,  what  was  happening  behind  the 
scenes  in  1992  and  1993  was  frightening.  These  researchers  knew 
that  from  zero  the  number  of  uterine  cancers  had  jumped  to  15  in 
the  tamoxifen  arm  of  the  trial,  and  4  of  those  women  had  died  of 
their  uterine  cancers.  Throughout  all  this  time  women  were  not  no- 
tified, doctors  taking  care  of  them  were  not  notified,  and  the 
healthy  women  volunteering  to  participate  in  the  prevention  trial 
were  not  notified. 

Finally,  in  November  1993  Dr.  Fisher  informed  NCI  of  the 
deaths.  Over  2  more  months  passed  before  Fisher  and  NCI  in- 
formed women  in  the  prevention  trial.  We  have  calculated  that 
over  600  women  were  given  a  consent  form  that  said  there  were 
no  deaths  from  uterine  cancer  after  the  NCI  had  been  informed 
about  deaths. 

This  is  very  disturbing,  but  unfortunately  it  isn't  even  the  worst 
of  the  misleading  information  that  has  been  given  to  women  by  Dr. 
Fisher  and  NCI.  Women  were  given  an  information  update  in  Jan- 
uary 1992.  It  told  them  that  the  increased  risk  of  breast  cancer  was 
approximately  threefold  compared  to  similar  women  in  a  general 
population. 

Well,  in  fact,  on  April  6  Dr.  Fisher  published  his  study  upon 
which  those  numbers  were  based  and  told  the  scientific  community 
in  the  NCI's  own  journal  that  the  risk  he  found  was  7.5  times  as 
high.  Women  in  the  prevention  trial  have  never  been  told  that. 
They  still  aren't  being  told  that  to  this  day.  They  are  being  given 
a  guesstimate,  and  a  guesstimate  that  is  far  lower  than  the  results 


22 

of  a  randomized,  placebo  controlled,  double  blind  trial,  the  scientific 
gold  standard  for  evidence. 

I  ask  the  committee  to  consider,  if  any  of  you  were  volunteering 
for  a  research  trial,  how  would  you  feel  if  you  were  told  that  a  risk 
of  a  complication  was  increased  by  three  times  and  you  later  found 
out  that  a  good  scientific  study  had  found  a  risk  of  7.5  times? 

This  pattern  of  behavior  has  resulted  in  the  general  public  being 
subjected  to  a  smoke  and  mirror  show  that  prevents  a  reasoned 
discussion  of  whether  the  trial  should  proceed. 

Because  of  this  behavior  on  the  part  of  Dr.  Fisher  and  NCI,  we 
have  come  to  the  state  where  Congressional  oversight  is  badly 
needed.  In  addition  to  the  types  of  changes  that  Ms.  Visco  has  de- 
scribed, which  we  agree  with  completely,  we  also  call  on  Congress 
to  ensure  that  there  is  an  appropriate  review  of  the  scientific  basis 
for  the  tamoxifen  prevention  trial,  and  any  appropriate  review  will 
have  to  be  conducted  by  an  agency  other  than  the  NCI  and  be  com- 
posed of  a  majority  of  prevention  experts,  public  health  experts,  not 
cancer  treatment  doctors. 

The  National  Women's  Health  Network  believes  that  this  trial 
should  be  stopped,  the  tamoxifen  prevention  trial  should  be 
stopped,  and  that  any  objective,  independent  review  will  come  to 
the  same  conclusion. 

Peter  Latham,  a  19th  Century  physician  said  that,  "Medicines 
and  poisons  are  oftentimes  the  same  substance  given  with  different 
intents." 

To  women  with  breast  cancer  tamoxifen  is  good  medicine.  To 
healthy  women  it  may  be  closer  to  poison. 

Thank  you. 

[The  prepared  statement  of  Ms.  Pearson  follows:] 


23 


Cynthia  A.  Pearson 

Program  Director 

National  Women's  Health  Network 

Adriane  Fugh-Berman,  MD 

Medical  Advisor 

National  Women's  Health  Network 

Good  morning.  Chairman  Dingell  and  members  of  the  Committee.    Thank  you  for  inviting 
us  to  participate  in  this  important  hearing. 

The  National  Women's  Health  Network  is  a  non-profit  women's  health  advocacy  group. 
We  are  financially  supported  by  our  membership  of  400  local  women's  health  projects  and 
over  17,000  individuals.    Our  mission  is  tvvo-fold:    to  advocate  for  better  federal  health 
policies  for  women,  and  to  provide  women  with  accurate,  useful  information  which  gives 
them  more  power  in  decisions  about  their  health  care. 

As  a  natural  outgrowth  of  those  goals,  the  Network  has  been  a  strong  supporter  of  clinical 
trial  research  for  women.    We  remember  all  too  vividly  the  harm  that  women  suffered  when 
they  were  treated  on  the  basis  of  hope  or  belief,  rather  than  scientific  knowledge.    The  use 
of  DES  in  healthy  pregnant  women  during  the  1950s  and  1960s  and  the  routine  use  of  fetal 
electronic  monitoring  in  low  risk  women  in  the  1980s  took  place  because  clinical  trials 
either  were  not  done,  or  were  ignored.    Women  and  their  babies  were  hurt,  not  helped,  by 
these  medical  interventions. 

In  addition  to  our  concern  that  all  aspects  of  women's  medical  care  be  based  on  well- 
founded  scientific  research,  the  Network  has  been  particularly  concerned  about  women's 
breast  cancer  treatment.    In  the  1970s,  surgical  treatment  for  breast  cancer  was  a  high 
priority  issue  for  the  newly  emerging  women's  health  movement.    Radical  mastectomy,  and 
the  "one-step"  biopsy/mastectomy  procedure  were  questioned  by  activists  and  authors  such 
as  Rose  Kushner  and  Barbara  Seaman.    American  women  learned  that  lumpectomy  was  an 
option  for  women  diagnosed  with  breast  cancer  who  lived  in  other  countries.    When  U.S. 
physicians  resisted  women's  requests  for  lumpectomy,  women  turned  to  the  research 
establishment  and  demanded  studies  that  would  convince  surgeons  that  lumpectomy  was 
safe. 

Those  studies  began  in  the  U.S.  and  other  countries  in  the  late  1970s.    The  researchers 
brave  enough  to  withstand  the  disdain  of  the  general  surgical  community  were  much 
applauded  by  women's  health  activists.    The  largest  of  these  trials  was  coordinated  by  Dr. 
Bernard  Fisher,  head  of  the  National  Surgical  Adjuvant  Breast  and  Bowel  Project  (NSABP). 


Dr.  Fisher  was  hailed  as  a  hero  by  many  in  the  women's  health  movement  as  well  as  the 
cancer  survivor  community.    Now,  nearly  twenty  years  later.  Dr.  Fisher  is  the  same  man 
who  has  been  found  to  demonstrate  such  utter  disregard  for  the  rights  of  patients  to  know 
the  results  of  research.    It  may  seem  ironic  that  we  have  come  today  to  criticize  the 
behavior  of  a  researcher  whom  previously  we  praised.    However,  it  is  vitally  necessary  that 
the  government  act  decisively  to  establish  clear  standards  to  protect  the  public's  right  to 
swift  and  full  disclosure  of  all  important  research  findings,  whether  good,  bad,  or 
embarrassing. 

As  a  consumer  group  our  biggest  complaint  about  the  behavior  of  Dr.  Fisher  and  the 
National  Cancer  Institute  (NCI)  is  the  delay  of  over  a  year  in  aimouncing  to  the  public  that 
falsified  data  were  submitted  to  NSABP.    Dr.  Fisher  and  NCI  also  delayed  releasing  a 


24 


reanalysis  of  previously  published  studies.    In  the  past,  NCI  has  rushed  Dr.  Fisher's  results 
to  the  public,  even  before  publication,  when  there  was  good  news.    To  delay  announcing 
the  falsification  of  data  within  the  breast  cancer  trials  makes  it  appear  that  Dr.  Fisher  and 
NCI  want  the  public  to  know  results  only  if  they  reflect  well  on  NSABP  and  NCI. 

This  disregard  for  the  public's  right  to  know  is  outrageous.    We  commend  Congress  for 
stepping  in  to  oversee  when  it  appears  that  NCI  isn't  able  to  assert  its  authority.    Dr.  Fisher 
seemingly  was  unable  or  unwilling  to  follow  NSABP's  own  gwdelines  for  auditing  of  data 
and  timely  reporting  of  possible  problems  with  data.   NCI  apparently  took  none  of  the 
appropriate  measures  that  would  ensure  compliance. 

Keeping  consumers  in  the  dark  has  been  a  theme  of  the  tamoxifen  prevention  trial  fiasco. 
Dr.  Fisher's  failure  to  report  problems  with  data  in  the  breast  cancer  treatment  trials  in  a 
timely  way,  and  NCI's  failure  to  require  compliance  with  standard  guidelines  for  auditing 
and  reporting  appear  to  be  paralleled  by  their  actions  with  regard  to  the  breast  cancer 
prevention  trial.   We  see  the  same  pattern  of  behavior.    Important  information  that 
volunteers  in  the  trial  and  the  general  public  need  to  know  is  withheld  for  unreasonably 
long  periods  of  time,  and  when  eventually  given  to  women  it  is  incomplete  and  misleading. 
This  pattern  of  behavior  has  important  consequences  for  women's  health,  and  important 
public  consequences  as  well.    By  withholding  information  about  the  effects  of  the  drug  used 
in  the  prevention  experiment,  NCI  and  Dr.  Fisher  are  attempting  to  sidestep  a  public 
discussion  of  the  wisdom  of  continuing  this  trial. 

The  breast  cancer  prevention  trial,  originally  a  bad  idea,  is  well  on  its  way  to  becoming  a 
disaster.    It  is  designed  to  give  healthy  women  tamoxifen,  a  breast  cancer  treatment  drug,  at 
the  same  dose  taken  by  patients  with  cancer.    The  trial  accepts  any  woman  over  the  age  of 
35  whose  risk  of  developing  breast  cancer  in  the  next  five  years  is  1.7  percent.    At  the  time 
this  trial  began,  the  known  serious  risks  of  the  drug  were  reported  to  be  almost  exactly 
equal  to  the  volunteers'  risk  of  developing  breast  cancer.    Specifically,  uterine  cancer  and 
blood  clots  occurred  in  1.8  percent  of  women  who  took  tamoxifen  for  five  years.    The  trial 
was  a  bad  idea  to  begin  with  because  it  wasn't  designed  to  test  whether  tamoxifen  could 
prevent  disease  in  healthy  women,  but  rather  to  determine  whether  one  disease  could  be 
substituted  for  another. 

Now,  we  find  that  the  risks  of  tamoxifen,  known  to  be  serious  at  the  time  the  trial  began, 
are  actually  much  worse.    We  believe  that  if  the  results  which  have  been  withheld  by  Dr. 
Fisher  had  been  openly  disclosed  when  the  trial  began  that  it  would  not  have  been 
approved.    We  also  believe  that  the  new  information  is  enough  justification  to  stop  the  trial. 
To  let  this  trial  proceed  is  to  watch  women  die  of  trust 

We  would  like  to  briefly  review  the  chronology  of  misinformation  by  omission  and 
commission  in  which  Dr.  Fisher  and  NCI  have  collaborated. 

In  April,  1992,  when  the  tamoxifen  prevention  trial  began,  women  were  given  a  consent 
form  that  told  them  the  risk  of  uterine  cancer  was  increased  by  about  three  times  based  on 
existing  data  from  several  large  trials  of  tamoxifen.    Women  \vere  told  that  nine  out  of 


25 


3,097  women  on  tamoxifen  developed  uterine  cancer  versus  four  out  of  3,091  women  not 
treated  with  tamoxifen.    These  numbers  were  based  on  a  1991  report  prepared  by  an  NCI 
scientist.  Dr.  Susan  Nayfield,  who  relied  upon  data  supplied  by  the  manufacturer  to  the 
FDA  in  1990.    By  1992,  NSABP  had  reports  of  four  more  tamoxifen-treated  women  who 
had  developed  uterine  cancer.    NSABP  included  this  information  in  the  prevention  trial 
protocol,  but  did  not  include  these  new  cancers  in  the  consent  form  that  women  were  given. 
If  the  most  up-to-date  information  had  been  given  to  women,  they  would  have  been  told 
that  the  risk  of  uterine  cancer  was  not  three  times  as  likely,  but  four  or  five  times  as  likely. 

In  addition,  the  1992  consent  form  assured  women  that  "no  deaths  from  uterine  cancer  were 
reported".    Again,  the  consent  form  was  seriously  misleading.    As  early  as  1991,  Dr.  Fisher 
and  NSABP  apparently  knew  that  a  tamoxifen-treated  patient  who  developed  uterine  cancer 
had  died.    But  instead  of  warning  women  of  this  possible  risk,  the  consent  form  told 
women  that  the  uterine  cancers  that  had  occurred  were  "thought  to  be  curable". 

The  1992  consent  form  was  misleading  in  other  ways,  as  well.   Women  were  told  that  a 
very  small  number  of  women  taking  tamoxifen  might  die  as  a  result  of  blood  clots.    What 
they  weren't  told  was  that  NSABP  had  found  that  a  much  larger  number  of  women  suffered 
life-threatening  blood  clots  which  required  hospitalization,  and  indefinite  treatment  with 
blood-thinning  medication.    Also,  women  were  told  that  liver  cancer  had  been  reported  in 
rats  receiving  tamoxifen  in  doses  greater  than  the  dose  used  in  humans.    Women  were  not 
told  that  the  manufacturer  of  tamoxifen  had  reported  to  the  FDA  in  a  public  hearing  that 
the  cancer-causing  dose  of  tamoxifen  in  rats  produced  levels  of  tamoxifen  in  the  blood  that 
were  equivalent  to  the  blood  levels  of  women  taking  tamoxifen  in  all  of  the  NSABP  trials. 

After  the  trial  began,  we  were  deeply  concerned  that  women  were  being  hoodwinked  into 
volunteering  for  a  trial  that  put  their  health  at  risk.    We  turned  to  Congress  for  help,  and 
worked  with  Congressman  Ted  Weiss,  who  chaired  the  Human  Resources  and 
Intergovernmental  Relations  Subcommittee  of  the  Committee  on  Government  Relations. 
The  Committee  conducted  an  inquiry  into  the  quality  of  the  informed  consent  forms  used  in 
the  tamoxifen  prevention  trial  and  found  shocking  results.    Two  hundred  and  sixty  eight 
forms  were  examined.    Sixty  eight  percent  either  omitted  or  altered  one  or  more  of  the  key 
points  from  the  model  consent  form  approved  by  NCI  reviewers.    To  put  it  bluntly,  NCI 
and  NSABP  had  allowed  a  bad  consent  form  to  become  worse.   Although  Mr.  Weiss  died 
as  the  inquiry  was  completed,  his  conunittee  held  hearings  chaired  by  Congressman  Donald 
Payne  in  October,  1992.   At  the  hearing,  the  Committee  members  attempt^  to  exercise 
their  oversight  function  by  questioning  the  underlying  scientific  basis  of  the  risks,  the 
possible  benefits  of  tamoxifen,  and  the  poor  quality  of  information  given  to  women 
volunteering  for  the  trial.   NIH  was  represented  by  Dr.  Healy  at  that  hearing.    Dr.  Healy 
resisted  all  efforts  of  the  committee  and  the  eventual  outcome  of  the  hearing  was  that  a  few 
consent  forms  which  didn't  even  meet  minimum  legal  requirements  for  informed  consent 
were  improved.    But  the  trial  continued  as  originally  planned. 

Since  the  last  time  Congress  reviewed  the  tamoxifen  prevention  trial,  more  evidence  about 
its  harm  has  been  published.    Liver  damage  in  women  on  tamoxifen  has  been  reported  to 
regulatory  bodies  in  both  the  U.S.  and  Britain.    Depression,  eye  damage  and  increased  rates 


26 

of  gastrointestinal  cancers  (including  liver  cancer)  have  been  reported.    Problems  with 
ovarian  function  in  premenopausal  women,  including  skyrocketing  estrogen  levels  and  large 
ovarian  cysts,  have  also  been  reported. 

As  these  reports  accumulated,  NSABP  and  NCI  were  silent  as  to  any  update  from  B-14,  the 
large  tamoxifen  treatment  trial  coordinated  by  Dr.  Fisher.    The  original  results  had  been 
published  in  1989.    No  updated  information  was  provided  throughout  1992  and  1993,  either 
to  the  general  public,  medical  journals,  or  those  who  received  the  prevention  protocol.    We 
have  now  discovered  that  what  was  happening  behind  the  scenes  was  frightening.    Uterine 
cancers  were  being  diagnosed  at  a  rapid  rate,  and  more  women  were  dying  as  a  result. 
From  zero  uterine  cancers  at  the  time  of  the  1989  publication,  to  six  as  of  May,  1991,  the 
number  jumped  to  1 5  in  the  tamoxifen  treated  arm  of  the  study.    And  still  women  weren't 
notified. 

Finally,  in  November,  1993,  Dr.  Fisher  informed  NCI  of  the  increased  incidence  of  uterine 
cancer  in  breast  cancer  patients  taking  tamoxifen,  and  of  the  four  deaths  from  uterine 
cancer.    Even  after  this  long  delay.  Dr.  Fisher  and  NCI  allowed  months  to  pass  before 
informing  women.    Throughout  all  of  1992  and  1993,  women  in  the  prevention  trial  were 
being  given  a  consent  form  that  falsely  reassured  them  that  uterine  cancer  was  not  fatal. 
Over  two  months  passed  after  Dr.  Fisher's  report  to  NCI  before  women  were  informed 
through  an  information  update.    We  have  calculated  that  nearly  600  women  were  given  a 
consent  form  that  said  there  were  no  deaths  from  uterine  cancer  after  NCI  had  been 
informed  about  the  deaths. 

This  is  very  disturbing,  but  unfortunately,  it  isn't  the  worst  of  the  misleading  information 
that  has  been  given  to  women  by  Dr.  Fisher  and  NCI.    The  information  update  given  to 
women  in  the  prevention  trial  in  January,  1994  accurately  informed  women  that  women 
taking  tamoxifen  had  died  from  uterine  cancer.    However,  it  also  told  women  that  the  risk 
of  developing  uterine  cancer  was  three  times  higher  than  a  similar  group  of  women  in  the 
general  population. 

It  wasn't  until  April  6,  when  Dr.  Fisher's  uterine  cancer  paper  was  fmally  published  in  the 
Journal  of  the  Nationd  Cancer  Institute  that  we  found  out  that  the  risk  of  developing 
uterine  cancer  for  women  in  the  NSABP  trial  was  not  three  times  as  high,  but  actually 
seven  and  one  half  times  as  high.     In  his  discussion.  Dr.  Fisher  attempted  to  minimize  his 
own  results.    With  NCI's  consent,  women  in  the  prevention  trial  were  told  a  "guesstimate" 
of  their  risk  for  uterine  cancer  that  was  far  lower  than  the  results  of  B-14.    A  "guesstimate" 
that  is  nowhere  close  to  the  risk  found  in  a  randomized,  placebo  controlled  trial  ~  the  gold 
standard  of  scientific  evidence.    We  would  ask  the  Committee  members  to  consider  whether 
if  they  were  volunteering  for  a  research  trial,  they  would  want  to  be  told  that  the  risk  of  a 
serious  complication  was  increased  by  three  times,  when  a  good  study  had  found  an 
increased  risk  of  seven. 

We  can't  impute  motive  to  Dr.  Fisher  and  NCI,  but  it  appears  as  if  they  don't  like  the 
results  of  the  NSABP  trials,  and  so  they  are  trying  to  avoid  others  becoming  aware  of 
unpopular  results.    Similar  to  NCI's  acquiescence.    Dr.  Fisher's  unwillingness  to  publish  a 


27 


reanalysis  of  the  NSABP  trial  affected  by  falsified  data,  NCI  has  allowed  Dr.  Fisher  to 
present  women  with  extremely  misleading  information  about  the  results  of  the  B-14  trial. 

This  pattern  of  behavior  has  resulted  in  the  general  public  being  subjected  to  a  smoke  and 
mirrors  show  that  prevents  a  reasoned  discussion  of  whether  this  trial  should  proceed.    NCI 
and  Dr.  Fisher  have  also  refused  to  respond  to  scientists  with  legitimate  critiques  of  the 
risks  and  possible  benefits  of  the  trial.    Last  fall,  two  important  reviews  of  the  prevention 
trial  were  published  by  credible  scientists  in  peer-reviewed  journals.    Neither  critique  has 
received  a  response.    To  consumer  advocacy  groups  it  appears  as  if  Dr.  Fisher  and  NCI 
don't  believe  that  along  with  public  trust,  and  public  tax  dollars,  comes  a  duty  to  participate 
in  public  discussion. 

In  summary,  the  National  Women's  Health  Network  is  convinced  that  Congressional 
oversight  is  necessary  in  this  case.    We  hope  that  there  will  be  two  results  from  this  effort 
We  call  for  an  increased  commitment  by  NCI  to  timely  disclosure  of  all  important 
information  from  clinical  trials.    We  also  call  for  the  establishment  of  a  system  to  ensure 
monitoring  and  follow  through  of  that  commitment. 

We  also  call  on  Congress  to  ensure  that  there  is  an  appropriate  review  of  the  scientific  basis 
for  the  tamoxifen  prevention  trial.   Any  appropriate  review  will  have  to  be  conducted  by  an 
agency  other  than  NCI  and  include  a  majority  of  prevention  and  public  health  experts,  not 
cancer  treatment  researchers.    The  National  Women's  Health  Network  belives  that  this  trial 
should  be  stopped  and  an  objective,  independent  review  will  come  to  the  same  conclusion. 
Peter  Merc  Latham,  a  19th  century  physician,  said  "medicines  and  poisons  are  oftentimes 
the  same  substance  given  with  different  intents".    To  women  with  breast  cancer,  tamoxifen 
is  good  medicine.    To  healthy  women,  it  is  closer  to  poiscm. 


28 

Mr.  DiNGELL.  Ms.  Sigal,  we  are  happy  to  welcome  you  here 
today.  The  time  I  last  saw  you  at  the  fund-raiser  that  we  were  par- 
ticipating in  I  was  not  aware  we  were  going  to  have  you  before  the 
committee.  I  notice  you  look  a  little  bit  uncomfortable.  I  want  you 
to  know  that  the  committee  is  known  for  having  sharp  teeth,  but 
we  are  also  known  for  being  careful  on  whom  we  use  them.  So  I 
hope  you  feel  comfortable  and  welcome. 

TESTIMONY  OF  JILL  LEA  SIGAL 

Ms.  Sigal.  Thank  you,  Mr.  Chairman.  I've  been  in  the  room 
when  you  have  exhibited  your  sharp  teeth,  so  I'm  glad  I'm  not 
going  to  get  that  today. 

Mr.  Chairman,  Mr.  Schaefer,  members  of  the  subcommittee,  my 
name  is  Jill  Sigal.  I  reside  in  Alexandria,  Virginia,  and  I  work  in 
Washington,  DC.,  as  a  consultant.  I  am  32  years  old  and  just  6 
months  ago  I  was  diagnosed  with  breast  cancer.  My  doctors  in- 
formed me  at  that  time  that  I  had  a  choice  in  surgical  procedures. 
I  could  either  have  a  lumpectomy  with  follow-up  radiation  or  a 
mastectomy. 

Loss  of  a  breast  is  a  difficult  prospect  for  any  woman.  Being  32, 
loss  of  a  breast  was  an  especially  frightening  option.  However,  if 
the  choice  was  between  having  one  breast  or  accepting  a  substan- 
tially higher  risk  of  premature  death,  the  choice  for  me  would  have 
been  a  clear  one.  I  would  have  opted  for  life. 

I  spent  the  2  weeks  between  the  time  of  my  biopsy  and  the  time 
of  my  surgery  talking  with  numerous  doctors  at  various  hospitals 
all  over  the  Washington  area  trying  to  gather  information  in  order 
to  make  an  informed  decision.  My  doctors  did  not  recommend  a 
particular  procedure  to  me.  They  left  the  decision  up  to  me.  My 
doctors  laid  out  the  facts  for  me  and  they  told  me  about  one  study 
that  concluded  that  a  lumpectomy  with  follow-up  radiation  had  the 
same  long-term  survival  rate  as  a  mastectomy.  The  study  that  my 
doctors  cited  to  me  is  the  study  that  is  in  question  today  that  we 
now  know  includes  falsified  data,  as  admitted  by  Dr.  Poisson. 

I  had  a  lumpectomy  and  I  based  my  decision  to  do  that  solely  on 
the  study  that  is  in  question  today.  Since  my  surgery  I  have  under- 
gone 6V2  weeks  of  radiation  and  I  am  currently  in  the  middle  of 
chemotherapy.  I  am  halfway  done. 

I  learned  only  2  weeks  ago  that  Dr.  Poisson  had  falsified  data 
and  therefore  the  results  of  the  study  are  being  questioned.  I  did 
not  learn  about  this  fraud  from  the  National  Cancer  Institute;  I  did 
not  learn  about  this  fraud  from  the  National  Surgical  Adjuvant 
Breast  and  Bowel  Project;  I  did  not  learn  about  this  fraud  from  the 
University  of  Pittsburgh  or  from  Dr.  Fisher.  I  learned  about  this 
fraud  because  one  day  I  was  looking  over  a  friend's  shoulder  who 
happened  to  be  reading  the  New  York  Times  and  a  headline 
jumped  out  at  me  talking  about  the  breast  cancer  fraud. 

I  understand  now  that  there  was  a  notice  in  the  June  21,  1993, 
Federal  Register  regarding  Dr.  Poisson.  I  went  back  this  week  and 
I  read  the  notice.  The  notice  doesn't  even  identify  the  study  in 
question.  Therefore,  if  I  had  read  the  Federal  Register  notice  back 
in  1993,  which  I  am  not  in  the  habit  of  reading  the  Federal  Reg- 
ister, I  would  not  have  known  what  it  was  referring  to  because  it 


29 

didn't  mention  the  lumpectomy  study.  Reading  the  notice  back  in 
1993  would  have  proved  to  be  of  no  use  to  me. 

My  anger  and  outrage  that  a  doctor  could  possibly  engage  in 
such  gross  scientific  fraud  was  surpassed  only  by  my  disbelief  when 
I  learned  that  the  National  Cancer  Institute,  an  instrument  of  the 
United  States  Government,  knew  about  the  falsified  data  3  years 
ago  and  deliberately  did  not  give  it  wide-spread  publicity. 

I  also  understand  that  the  University  of  Pittsburgh  knew  about 
the  falsified  data  3  years  ago  and  deliberately  did  not  give  it  wide- 
spread publicity.  I  also  understand  that  the  University  of  Pitts- 
burgh knew  about  the  fraud  approximately  4  years  ago,  and  it 
withheld  the  information  from  the  National  Cancer  Institute  for  a 
period  of  time.  These  organizations  did  not  inform  the  public.  They 
did  not  even  inform  the  doctors  who  could  have  then  advised  their 
patients  accordingly. 

How  many  women  during  these  3  years  made  a  decision  about 
their  surgery,  as  I  did,  based  on  this  study.  How  many  women 
must  now  wonder,  as  I  do  every  day,  if  they  will  die  because  they 
may  have  made  the  wrong  decision?  How  many  women,  Mr.  Chair- 
man, will  die?  We  will  never  know. 

If  my  cancer  returns,  it  is  likely  to  come  back  in  my  liver,  my 
lungs,  or  my  bones.  My  doctors  tell  me  that  if  this  happens,  my 
cancer  cannot  be  cured  and  I  will  die.  If  this  happens,  my  family 
and  friends  will  never  know  if  my  cancer  had  spread  prior  to  my 
operation  and  there  really  wasn't  much  that  anybody  could  do  or 
whether  the  reoccurrence  was  due  to  the  fact  that  I  had  a 
lumpectomy  instead  of  mastectomy. 

I  take  no  comfort,  no  comfort  whatsoever  from  the  fact  that  the 
Institute  that  swept  the  fraud  under  the  rug  for  3  years  now  claims 
to  have  conducted  a  re-analysis  of  the  study  and  maintains  that 
the  findings  are  still  valid.  For  me,  the  National  Cancer  Institute 
has  forfeited  any  claim  to  credibility.  Indeed,  I  understand  that 
when  the  National  Cancer  Institute  first  announced  to  the  public 
that  it  had  conducted  a  re-analysis,  the  announcement  was  false. 
It  was  only  later,  from  my  understanding,  that  a  re-analysis  was 
actually  conducted,  and  even  then  the  so-called  re-analysis  did  not 
include  a  review  of  the  raw  data. 

Mr.  Chairman,  there  seems  to  be  no  end  to  the  fraud  and  decep- 
tion. As  a  result  of  the  National  Cancer  Institute's  behavior  in  this 
manner,  I  now  question  other  policies  of  the  National  Cancer  Insti- 
tute, including  its  policy  that  women  under  the  age  of  50  should 
not  get  a  mammogram  unless  they  are  at  high  risk. 

Well,  Mr.  Chairman,  I  don't  think  there's  a  doctor  in  the  world 
that  would  say  that  I  was  at  high  risk.  In  fact,  the  doctors  that  are 
treating  me  have  told  me  that  my  chance  of  getting  breast  cancer 
at  age  32  was  0.2  percent.  My  cancer  had  been  growing  inside  me 
for  several  years.  If  I  had  had  a  mammogram  a  year  or  two  ago, 
I  would  have  possibly  caught  the  cancer  at  its  earliest  stage  when 
it's  contained  within  the  duct,  and  the  survival  rate  would  have 
been  for  me  then  approximately  98  percent.  Well,  my  cancer  was 
not  caught  at  this  stage.  I  had  invasive  cancer,  and  my  chance  of 
survival  is  far  less  than  98  percent.  If  I  had  had  a  mammogram 
earlier,  I  very  likely  would  not  be  facing  the  daily  fear  of  pre- 
mature death. 


30 

Mr.  Chairman,  there  is  nothing  that  this  subcommittee  can  do  to 
help  me.  My  fate  is  cast,  but  there  are  several  things  that  this  sub- 
committee can  do  under  your  leadership  to  prevent  similar  atroc- 
ities from  occurring  in  the  future.  I'm  no  expert  in  this  area  of 
breast  cancer,  but  I  ask  the  subcommittee  to  consider  the  following 
recommendations,  some  of  which,  based  on  your  opening  statement, 
Mr.  Chairman,  I  understand  may  be  currently  underway. 

First,  I  ask  the  subcommittee  to  consider  commissioning  an  inde- 
pendent re-analysis  of  the  study  and  the  raw  data  with  a  written 
report  to  be  submitted  to  the  subcommittee  within  60  days.  The  re- 
port should  be  published  and  made  available  to  the  public. 

Two,  order  the  release  of  the  raw  data  with  the  names  of  the  pa- 
tients redacted. 

Three,  prohibit  the  National  Cancer  Institute  from  awarding  any 
grants  to  the  University  of  Pittsburgh  for  5  years,  or  until  after  a 
thorough  study  of  its  procedures  and  safeguards  has  been  con- 
ducted. 

Four,  extend  the  8  year  debarment  of  Dr.  Poisson  from  receiving 
Federal  grants  to  a  lifetime  prohibition. 

Five,  change  the  way  allegations  of  scientific  fraud  are  inves- 
tigated by  the  National  Cancer  Institute  and  the  Federal  Office  of 
Research  Integrity,  including  requiring  timely  widespread  notifica- 
tion of  scientific  fraud. 

The  fear  that  arises  from  facing  one's  own  mortality  at  my  age 
can  at  times  be  paralyzing.  Now,  as  a  result  of  this  fraudulent 
study,  and  the  apparent  cover-up  by  the  National  Cancer  Institute 
and  the  University  of  Pittsburgh,  my  terror  is  exacerbated.  Today 
there  exists  a  crisis  of  confidence  and  credibility  as  it  pertains  to 
the  National  Cancer  Institute  and  to  the  other  Organizations  associ- 
ated with  this  study.  Even  if  the  conclusion  of  the  study,  Mr. 
Chairman,  holds  up  after  a  proper  re-analysis,  think  about  the 
agony  of  uncertainty  that  I  and  thousands  of  others  are  currently 
enduring. 

I  thought  I  had  made  an  informed  decision,  and  I  thought  I  had 
done  everything  in  my  power  to  increase  my  chances  of  enjoying  a 
normal  life  expectancy.  Now,  I  must  wonder  every  day  if  I  really 
have  done  everything  to  maximize  my  chances  of  survival. 

If  the  members  of  this  subcommittee  can  save  just  one  life,  then 
in  my  very  humble  opinion,  you  will  have  accomplished  a  lifetime 
achievement  as  a  member  of  the  House  of  Representatives.  That 
life  you  save  may  be  somebody  you  know.  I  do  not  understand  how 
I  got  breast  cancer,  but  I've  come  to  accept  it,  and  I  deal  with  it 
as  best  I  can.  What  I  cannot  understand  and  cannot  accept  is  why 
a  medical  doctor  would  falsify  data  in  a  study  that  was  intended 
to  guide  thousands  in  making  what  could  be  a  life  or  death  deci- 
sion, and  why  the  people  given  the  responsibility  to  oversee  the 
study  did  not  publicize  the  fraud  immediately. 

I  would  like  and  need  answers  to  these  questions,  Mr.  Chairman. 
To  me,  this  hearing  is  not  just  about  breast  cancer.  To  me,  this 
hearing  is  about  accountability.  The  people  have  a  right  to  have 
faith  and  confidence  in  U.S.  government  sponsored  research.  These 
recent  events  show  us  clearly  that  the  process  has  failed.  Mr. 
Chairman,  you  and  your  committee  have  the  authority  and  the 


31 

power  to  diminish  or  eliminate  the  possibility  of  this  atrocity  from 
ever  happening  again  by  changing  and  strengthening  the  process. 

Mr.  Chairman,  Mr.  Schaefer,  thank  you  from  the  bottom  of  my 
heart  for  holding  this  hearing  and  for  doing  what  you  can  to  correct 
this  grave  injustice. 

Mr.  DiNGELL.  Thank  you,  Ms.  Sigal,  for  your  most  helpful  state- 
ment. Be  assured  that  we  intend  to  pursue  this  matter  with  the 
usual  vigor  that  this  subcommittee  has  displayed  over  the  years, 
and  I  would  say  that  there  are  a  number  of  people  out  there  who 
probably  will  rest  poorly  being  aware  of  that  information.  I  will  ob- 
serve parenthetically  that  we  will  anticipate  hearing  from  the  Uni- 
versity of  Pittsburgh.  I  know  they're  looking  forward  for  a  chance 
to  come  forward  and  tell  their  side  of  the  story,  as  we  are  looking 
forward  to  a  chance  to  hear  their  side  of  the  story  and  perhaps  ask 
them  a  few  simple  little  questions. 

Ms.  SiGAL.  Well,  I  take  great  confidence  in  that,  Mr.  Chairman. 
Thank  you  very  much. 

Mr.  DiNGELL.  Well,  be  assured  we  will  follow  this  matter  forward 
vigorously. 

Ms.  Sigal.  Thank  you,  sir. 

Mr.  DiNGELL.  Your  statement  has  been  most  impressive,  and  we 
thank  you  for  your  assistance. 

Ms.  Sigal.  Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  is  now  going  to  recognize  members  of 
the  committee  in  the  order  prescribed  by  the  rules.  The  Chair  rec- 
ognizes first  the  gentleman  from  Colorado,  Mr.  Schaefer. 

Mr.  Schaefer.  Thank  you  very  much,  Mr.  Chairman.  I  do  appre- 
ciate the  testimony  of  all  three  members  before  the  committee 
today.  We  know  that  a  dreadful  situation  has  developed,  not  only 
with  the  people  involved  but  the  Cancer  Institute,  and  I  think 
we're  all  very  interested  in  getting  to  them  a  little  bit  later  on.  I 
would  ask  Ms.  Sigal,  you  testified  that  you  first  learned  of  the  fal- 
sifications of  the  research  data  from  news  reports.  Is  that  right? 
Your  doctor  did  not  know? 

Ms.  Sigal.  No.  I  was  reading  over  a  friend's  shoulder  who  was 
reading  the  March  27  edition  of  the  New  York  Times,  and  this 
headline,  "Federal  Officials  to  Review  Documents  in  Breast  Cancer 
Study,  jumped  out  at  me.  That's  the  way  I  found  out  about  it.  I 
went  to  my  doctor  after  I  read  this  and  I  asked  him  if  he  knew. 
He  found  out  about  it  the  same  way,  reading  about  it  in  the  paper. 

Mr.  Schaefer.  Ms.  Visco? 

Ms.  Visco.  Mr.  Schaefer,  that's  exactly  how  I  found  out  about  it, 
and  I  think 

Mr.  Schaefer.  By  the  newspaper? 

Ms.  Visco.  By  the  newspaper.  I  think  it's  particularly  egregious, 
you  know,  my  organization  in  October  presented  the  President  with 
2.6  million  signatures  on  a  petition  from  women  and  men  and  chil- 
dren across  this  country  asking  for  a  national  action  plan  for  breast 
cancer,  and  the  President  said  yes.  At  his  request,  Secretary 
Shalala  hosted  a  conference  of  the  National  Institutes  of  Health  on 
December  14  where  we  had  consumer  activists,  government  rep- 
resentatives, scientific  community  representatives,  private  indus- 
try, the  media,  and  representatives  from  Congress,  come  together 


32 

to  sit  at  a  table  and  begin  the  design  of  a  national  action  plan,  and 
we  shared  ideas  and  facts  and  concepts. 

I  feel  quite  foolish  today  thinking  back  on  that  day  because  I 
thought  we  were  there  at  the  table  on  a  level  playing  field,  and  I 
find  out  there  was  very  important  information  that  was  kept  from 
us.  If  it  was  ever  going  to  be  told  to  us,  even  belatedly,  it  should 
have  been  that  day,  and  it  was  not.  So  yes,  I  found  out  about  it 
from  the  newspaper. 

Ms.  Pearson.  Mr.  Schaefer? 

Mr.  Schaefer.  Yes? 

Ms.  Pearson.  I  read  the  Federal  Register  each  day.  Maybe  I'm 
one  of  the  few,  but  it's  part  of  my  job.  I  look  at  the  table  of  contents 
and  then  I  read  the  notices  specific  to  women's  health,  and  even 
I  couldn't  find  it.  That  notice  in  June  was  buried.  There  was  no 
way  any  reader  could  tell  its  importance. 

Mr.  Schaefer.  Don't  you  think — is  there  any  responsibility  on 
the  physicians  themselves  to  look  at  this?  I  mean,  your  doctors, 
they  should  have  been  at  least  told  of  what  was  going  on,  it  seems 
to  me.  How  can  they  advise  you,  even  though  they  give  the  final 
decision  to  you  on  whether  you  have  a  lumpectomy  or  a  mastec- 
tomy? Shouldn't  this  data  be  submitted  to  them  on  a  continual 
basis? 

Ms.  SiGAL.  Absolutely,  Mr.  Schaefer.  I  mean,  without  this  infor- 
mation being  given  to  the  doctors,  the  doctors  can't  advise  people 
like  myself  adequately.  I  mean,  my  doctors  did  a  great  job.  I'm  very 
proud  of  the  doctors  that  are  caring  for  me,  and  they  gave  me  the 
best  advice  they  could  and  they  laid  out  the  facts  as  we  knew  them 
back  then  in  October,  just  6  months  ago.  If  they  had  had  this  infor- 
mation, I  would  have  seriously  considered  whether  or  not  the  risk 
was  worth  it  of  going  through  with  a  lumpectomy,  and  I  probably 
would  have  gone  forward.  As  difficult  as  it  would  have  been  emo- 
tionally for  me,  I  probably  would  have  had  the  mastectomy  in  order 
to  maximize  my  chances  of  living,  because  that's  what  this  is  all 
about. 

Mr.  Schaefer.  Ms.  Visco,  how  long  was  it  ago  that  you  have  a 
lumpectomy? 

Ms.  VisCO.  September  1987. 

Mr.  Schaefer.  And  you  have  gone  back  and  been  checked  over 
this  period  of  time? 

Ms.  Visco.  Yes. 

Mr.  Schaefer.  And  there  hasn't  been  any  recurrence  or  any- 
thing? 

Ms.  ViSCO.  I  have  not  been  diagnosed  with  a  recurrence,  that's 
correct. 

Mr.  Schaefer.  Well,  we're  all  glad  of  that.  I  know  you  are. 

Ms.  Visco.  Yes. 

Mr.  Schaefer.  But  again,  it's  a  decision  that  you  made  at  that 
time,  in  1987,  and  so  it's  worked  out  all  right. 

Ms.  VisCO.  I  understand  the  studies.  I  understand  that  there  are 
independent  studies  that  support  the  results  of  the  NSABP  spon- 
sored trial.  I  understand  that.  I  think  most  women  with  breast  can- 
cer do  understand  that,  but  we  do  live  every  day  with  the  threat 
of  a  recurrence  hanging  over  our  heads  because  we  don't  know  how 
to  cure  this  disease.  That  level  of  concern  is  with  me  every  single 


33 

day,  and  now  on  top  of  that,  I  have  a  new  level  of  concern.  It's  un- 
necessary. It  doesn't  need  to  be  there.  This  information — I'm  sure 
there's  fraud.  I  mean,  you  cannot  guarantee  that  there's  never 
going  to  be  fraud,  but  once  you  find  out  about  it,  do  something 
about  it. 

Mr.  SCHAEFER.  I  think  this  is  right.  My  time  is  about  up  here, 
Mr.  Chairman,  but  I  think  Ms.  Sigal  hit  it  right  on  the  head.  We're 
not  only  talking  about  this  particular  study  and  what  the  Cancer 
Institute  has  withheld  or  who  has  withheld  what.  We're  talking 
about  trust  in  the  government  on  what  information  they  dissemi- 
nate to  the  people.  I  think  this  is  the  bottom  line  that  chairman 
wants  to  get  at.  I  too  would  like  to  do  that.  So,  I  certainly  appre- 
ciate your  testimony  here  today,  and  we'll  do  all  that  we  can  in 
working  with  the  chairman  to  make  sure  this  does  not  ever  happen 
again. 

Mr.  DiNGELL.  Will  the  gentleman  yield  to  the  Chair  just  very 
briefly?  I  just  want  to  maJce  a  comment.  We  have  gone  through 
these  questions  of  scientific  misconduct,  fraud  and  things  of  that 
kind.  One  of  the  things  that's  been  most  comforting  to  the  Chair 
has  been  the  wonderful,  cooperative  way  with  which  all  of  my  col- 
leagues on  this  subcommittee  have  cooperated  with  the  Chair  in 
these  investigations,  particularly  the  gentleman  from  Colorado.  It 
has  been — we  have  had  great  difficulties,  as  the  gentleman  very 
well  recalls.  The  committee  has  been  under  attack  for  having  in- 
sisted that  the  question  of  scientific  misconduct  and  scientific  fraud 
be  addressed  internally  inside  the  scientific  community,  and  also 
that  Federal  agencies  address  their  question  and  the  responsibility. 

We've  also  dealt  with  it  up  until  now  from  the  standpoint  of  the 
concern  that  we  had  and  the  jurisdictional  responsibility  we  had 
about  the  funding  with  Federal  dollars.  Today,  because  of  the  com- 
ments of  Ms.  Sigal,  Ms.  Visco,  and  Ms.  Pearson,  we're  seeing  it  now 
from  a  more  personal  standpoint,  from  the  hurt,  the  danger,  the 
peril,  the  trauma  that  it  occasions  to  citizens  who,  interestingly 
enough,  are  taxpayers  who  support  these  programs,  who  are  enti- 
tled to  openness  and  truth,  who  are  entitled  to  honorable  and  prop- 
er behavior  by  investigators,  and  proper  discipline  within  the  sci- 
entific community  and  within  the  government  itself.  Regrettably, 
we're  not  seeing  that,  but  my  comments  to  the  gentleman  particu- 
larly are  my  gratitude  to  him  and  the  members  of  the  committee. 
My  commendations  to  him  for  the  faithful  and  vigorous  and  decent 
way  in  which  he  has  stood  with  the  Chair  as  we've  gone  through 
some  very  hard  times  in  these  investigations.  So,  I  express  my 
thanks  to  the  gentleman  at  this  time,  as  I  do  to  the  rest  of  the 
members  of  the  committee. 

The  Chair  recognizes  now  the  gentlewoman  from  Illinois  for 
questions. 

Ms.  Collins.  Thank  you,  Mr.  Chairman.  Ms.  Sigal,  I  must  say 
that  your  testimony  was  most  impressive,  and  one  that  I  don't 
think  I'll  ever  forget.  I  certainly  can't  say  that  of  a  great  many  oth- 
ers that  I  have  heard,  not  on  this  subject  but  on  any  subject  as  a 
matter  of  fact.  Let  me  say  that  I  think  that  you  have  done  the 
country,  and  particularly  those  of  us  who  are  interested  in  this 
matter,  a  tremendous  favor  by  coming  to  us  and  giving  us  your  per- 
sonal testimony  on  what  has  happened  as  a  direct  result  of  the  in- 


34 

formation  that  you  did  not  have  to  avail  yourself  of  regarding  a 
treatment  that  you  could  have  chosen,  and  I  personally  thank  you 
for  that.  We  all  have  a  debt  of  gratitude  that  we  owe  you. 

The  chairman  has  already  said  that  we're  going  to  have  people 
in  from  Pittsburgh  to  answer  some  questions  about  why  this  was 
not  revealed  to  you  and  to  many  other  people,  and  we're  also  going 
to  receive  testimony  at  this  hearing  and  the  others  from  the  NIH 
and  the  NCI.  They  would  have  us  to  believe  that  the  issue  here  is 
simply  probably  that  the  conclusions  of  the  lumpectomy/mastec- 
tomy  trial  are  still  valid.  Do  any  of  you  at  the  table  think  that  the 
conclusions  are  still  valid? 

Ms.  Pearson.  This  is  interesting,  Ms.  Collins,  because  in  the 
70's,  lumpectomy  was  something  that  women  demanded.  We  heard 
that  it  was  available  to  women  in  other  countries.  They  seemed  to 
be  surviving  as  long,  but  American  surgeons  resisted.  So  we,  and 
some  in  the  cancer  research  community  called  for  trials,  and  that's 
why  I  opened  by  saying  what  a  strong  supporter  we  were  of  re- 
search. We  were  delighted  that  the  lumpectomy  trial  began  in  the 
United  States,  and  when  it  reported  the  results,  we  joined  the  Na- 
tional Cancer  Institute  in  encouraging  women  to  consider 
lumpectomy.  We  know  that  there  were  five  other  trials  conducted 
independent  of  NCI  and  NSABP,  some  in  other  countries,  that 
have  found  similar  results. 

So,  if  the  NCI  and  NSABP  had  had  the  sense  and  just  the  de- 
cency to  come  forthrightly  immediately  and  say  we  found  this 
fraud.  It's  horrible.  We'll  make  sure  it  never  happens  again,  here's 
our  re-analysis.  We  think  our  trial  is  still  the  same,  and  there's 
these  five  other  trials.  Women  would  have  had  some  worry,  of 
course,  but  it  could  have  been  handled  much  more  usefully  if  we 
had  gotten  the  whole  package  of  information  all  at  once.  Now  it 
comes  out  as  if  there's  a  cover-up,  and  it's  hard  for  women  to  even 
get  the  information  that  there  are  several  other  trials  that  show 
lumpectomy  as  effective  as  mastectomy. 

Ms.  Visco.  I  echo  what  Ms.  Pearson  said.  I  also  want  to  add  that 
I  think  the  fact  that  fraud  was  going  on  for  13  years  and  the  fact 
that  whatever  procedures  were  in  place  were  unable  to  detect  that, 
and  the  fact  that  the  NCI  wasn't  aware  of  that  for  quite  some  time, 
that  has  to  be  put  into  the  mix  also.  Although  we  do  recognize  that 
there  are  other  studies  reporting  the  result,  the  concern  in  the  pub- 
lic trust  is  affected.  When  you  look  at  that  and  say  well,  what  else 
is  out  there?  If  these  are  the  procedures  and  they  didn't  work  here 
and  they  got  caught  here,  what  else  is  out  there  that  we  don't  know 
about?  We  need  to  do  something  about  these  procedures. 

Ms.  Collins.  Exactly.  Ms.  Sigal? 

Ms.  Sigal.  Mrs.  Collins,  first  of  all,  thank  you  very  much  for 
those  kind  remarks.  I  think  it's  premature  to  say  whether  the  con- 
clusion of  the  lumpectomy  study  is  still  valid.  I  personally  have  a 
big  problem  with  anything  the  National  Cancer  Institute  has  said 
and  probably  will  say  today.  It's  not  going  to  comfort  me.  As  Ms. 
Visco  said,  this  has  been  going  on  for  13  years.  I  think  what  needs 
to  be  done  is  we  need  to  have  a  proper  re-analysis  of  the  study.  I 
don't  take  their  word  for  it.  I  can't  because  my  life  is  depending  on 
this,  as  well  as  hundreds  of  thousands  of  other  women.  So,  for 
them  to  tell  me,  oh,  you're  going  to  be  OK,  that  doesn't  mean  any- 


35 

thing  to  me  today.  I  don't  think  it  means  anything  to  my  sister 
who's  sitting  behind  me  or  my  mother,  who's  watching.  No,  we 
need  to  have  a  proper  re-analysis  and  a  review  done. 

As  regards  to  tne  other  studies,  when  I  made  my  decision,  I 
never  knew  that  other  studies  existed  because  my  doctors,  I  as- 
sume, felt  that  the  study  in  question  today  was  the  pre-eminent 
study  and  that  is  the  only  one  that  they  told  me  about.  It  wasn't 
until  last  Friday  when  I  went  racing  to  my  doctor  to  talk  to  him 
about  all  of  this,  when  I  went  to  have  my  chemotherapy  treatment, 
that  he  said  well,  Jill,  there  are  other  studies  that  exist.  Well,  but 
I  share  Ms.  Visco's  view.  Well,  if  it  could  happen  in  one  study, 
maybe  it  could  happen  again.  I  don't  want  to  believe  that.  I  do 
want  to  have  faith  in  what  government  sponsored  research  tells  us, 
but  I  think  there's  a  credibility  gap.  I  think  with  your  help  and  the 
chairman's  and  this  committee's,  that  you  could  fix  that. 

Ms.  Collins.  Thank  you.  Ms.  Visco,  NCI  and  HHS  officials  have 
expressed  their  concerns  about  due  process  and  fairness.  They  be- 
lieve it  was  best  to  not  tell  the  public  about  the  unreliable  St.  Luc's 
data  until  after  the  conclusion  of  the  ORI  investigation.  Have  you 
thought  about  whether  HHS  could  have  preserved  fairness  while 
also  honoring  the  public's  right  to  know  and  what  strategies  might 
HHS  have  pursued  in  this  regard? 

Ms.  VisCO.  Yes.  As  a  breast  cancer  survivor  and  as  an  attorney, 
I  did  give  that  quite  a  bit  of  thought.  The  process  should  not  have 
taken  that  long.  The  information  could  have  been  released  to  the 
public  much  earlier.  Simply,  the  investigation  should  not  have 
taken  that  long.  Dr.  Poisson  admitted  falsifications.  In  addition, 
the  NCI  had  the  information  and  the  investigation  was  complete, 
I  believe  the  latest  date  I've  heard  is  last  spring,  the  spring  of  '83. 
We're  just  finding  out  about  it  today,  and  from  the  newspaper.  So, 
I  do  believe  that  whatever  process  is  in  place  to  investigate  has  to 
be  shortened,  and  I'm  certain  that  it  can  be. 

Ms.  Collins.  Thank  you.  Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentlewoman.  The  Chair  rec- 
ognizes now  the  gentlewoman  from  Pennsylvania,  Ms.  Margolies- 
Mezvinsky. 

Ms.  Margolies-Mezvinsky.  Thank  you,  Mr.  Chairman.  Ms. 
Sigal,  today  we  hear  testimony  that  in  1992,  NCI  and  HHS  officials 
failed  to  recognized  that  Dr.  Fisher  had  not  re-analyzed  his  data 
showing  the  recurrence  of  a  tumor  in  the  ipsilateral  breast  for  la- 
dies that  had  had  a  lumpectomy.  But  these  same  NCI/HHS  officials 
have  told  subcommittee  staff  that  the  absence  of  re-analvsis  of  this 
data  was  not  important  because  occurrence  of  ipsilateral  tumors  is 
a  secondary  variable,  a  minor  consideration  they  said.  As  a  women 
who  just  6  months  ago  had  a  lumpectomy,  what's  your  reaction  to 
this  kind  of  thinking? 

Ms.  Sigal.  Well,  it  may  not  be  important  to  the  people  in  the  Na- 
tional Cancer  Institute,  but  I  can  tell  you  it  is  certainly  important 
to  me  and  to  my  family  and  my  friends,  who  don't  want  to  see  me 
die  because  of  this.  So,  my  reaction  to  your  statement  is,  I  think 
that's  an  outrageous  thing  for  the  National — and  inhumane  thing 
for  the  National  Cancer  Institute  to  say.  It's  that  kind  of  attitude 
that  I  think  has  led  to  this  problem.  I  think  people's  egos  have  got- 
ten in  the  way  of  scientific  integrity  in  research,  and  I  believe  that 


36 

there  has  to  be  some  kind  of  reviewability  for  these  scientists.  If 
there's  nothing  to  hide,  then  why  not  open  up  the  process? 

Ms.  Margolies-Mezvinsky.  What  did  your  doctor  say  to  you? 

Ms.  SiGAL.  My  doctor  tried — I  was  there  on  Friday  when  I  had 
my  treatment,  and  I  was  quite  upset.  He  said  that  there  are  other 
studies.  Like  I  was  telling  Mrs.  Collins,  I  did  not  know  about  that 
at  the  time  when  I  made  my  decision  to  have  a  lumpectomy  in  Oc- 
tober, but  he  said  that  there  are  other  studies  and  that  everything 
is  going  to  be  OK.  Well,  I  have  great  faith  in  my  doctor,  I  really 
do,  but  I  would  greatly  appreciate  if  we  could  have  a  proper  re- 
analysis  because  until  that  is  done,  until  it  is  done  by  some  entity 
that's  not  connected  with  the  National  Cancer  Institute,  yes,  I  will 
still  worry.  My  family  will  still  worry,  and  I'm  sure  that  thousands 
and  tens  of  thousands  of  women  who  are  out  there  in  the  same  po- 
sition that  I  am  will  worry  as  well. 

Ms.  Margolies-Mezvinsky.  Did  your  doctor  say  anything  about 
Dr.  Fisher? 

Ms.  SiGAL.  Yes,  he  did.  He  was  actually  very  complimentary  of 
Dr.  Fisher.  I  personally  can't  speak  to  Dr.  Fisher.  I  don't  really 
know  much  about  what  he  has  done  except  for  what  I've  read  in 
the  papers,  and  it  does  sound  very  good,  but  yes,  my  doctor  was 
very  complimentary  of  him.  In  fact,  he  even  said,  "We  don't  need 
to  throw  the  baby  out  with  the  bath  water."  He  did  say  that.  I 
looked  at  him  and,  quite  frankly,  while  I  was  getting  shot  up  in  the 
veins  during  my  chemotherapy  treatment,  we  had  quite  a  heated 
discussion  about  this  whole  subject  for  the  hour  that  I  was  there. 
I'm  not  sure  in  this  particular  instance  that  I  agree  completely 
with  what  my  doctor  thinks  in  this  instance,  but  I  do  have  faith 
in  the  way  he's  treating  me. 

Ms.  Margolies-Mezvinsky.  If  Dr.  Fisher  and  his  colleagues 
were  here  today,  is  there  any  message  that  you  would  like  to  share 
with  them  over  and  above  what  you  said  in  your  testimony? 

Ms.  SiGAL.  I'm  not  sure  there's  a  message  that  I'd  like  to  send, 
but  there  are  certainly  questions  that  I  would  want  to  ask  Dr. 
Fisher,  like  why.  I  want  to  know  why.  I  want  to  know  why  the 
process  broke  down.  I  want  to  know  why  the  procedures  weren't 
followed,  their  own  procedures,  the  procedures  of  the  National  Can- 
cer Institute  and  the  National  Institute  of  Health.  I  want  to  know 
why  the  audits  weren't  conducted  over  the  last  year  because  I  don't 
understand.  Is  there  some  scientific  reason?  Did  somebody's  ego  get 
in  the  way?  I  don't  know,  but  that's  what  I'd  like  to  know  from  Dr. 
Fisher  and  the  University  of  Pittsburgh.  Why  did  he  allow  this  to 
happen? 

Ms.  Margolies-Mezvinsky.  The  other  panel  members? 

Ms.  Visco.  I  would  like  to  speak  for  a  moment  to  an  issue  that 
you  raised  earlier,  and  that  is  the  fact  that  there  apparently  were 
some  findings  of  recurrence  but  not  mortality,  and  they  were  not 
considered  statistically  significant.  This  also  speaks  to  the  position 
that  my  organization  takes,  and  I  know  that  Ms.  Pearson's  organi- 
zation also  supports,  and  that  is  we  women  with  breast  cancer  and 
consumer  advocates  should  be  involved  because  I  have  been  to  a 
number  of  meetings  where  the  scientific  community  has  spoken 
about  what  they're  looking  at  is  the  mortality  rate. 


37 

We  keep  raising  the  issue  of  well,  what  about  recurrence?  What 
about  quality  of  life?  What  about  these  issues?  Mortality,  how 
many  women  live  and  died  is  not  the  only  question  we  should  be 
looking  at.  In  this  trial,  let's  look  at  the  women  who  had 
lumpectomies  rather  than  mastectomies.  How  many  recurrences 
were  there?  Those  are  not  questions  that  the  scientific  community 
have  asked.  If  women  were  at  the  table,  those  questions  would  be 
asked. 

Ms.  Pearson.  I  guess  what  I  would  say  to  Dr.  Fisher  is  that  he 
seems  to  have  lost  the  understanding  that  with  public  funds  and 
public  trust  needs  to  come  a  commitment  to  public  discussion.  As 
I  described  in  my  testimony,  there's  been  an  apparent  pattern  of 
behavior  of  believing  that  Dr.  Fisher,  NSABP  and  to  some  extent 
the  NCI,  can  decide  for  themselves  what  the  public  needs  to  know 
and  what  they're  willing  to  talk  about  with  the  public.  I  would  just 
want  to  let  Dr.  Fisher  know  that  we  disagree  strongly  with  that. 

Ms.  Margolies-Mezvinsky.  Thank  you.  Mr.  Chairman,  I  yield 
back  the  balance  of  my  time. 

Mr.  DiNGELL.  The  time  of  the  gentlewoman  has  expired.  The 
Chair  recognizes  now  the  gentleman  from  Ohio,  Mr.  Brown. 

Mr.  Brown.  Thank  you,  Mr.  Chairman.  Ms.  Pearson,  is  it  pos- 
sible for  NCI/HHS  to  regain  the  trust  of  the  public,  particularly  the 
trust  of  women  at  risk  for  and  diagnosed  with  breast  cancer? 

Ms.  Pearson.  I  think  it  is,  yes,  because  if  they  can't  we're  in  big 
trouble.  We'll  never  have  scientific  grounding  for  our  treatment  de- 
cisions, and  we  know  that  we  desperately  need  that.  I  think  NCI 
and  HHS  need  to  take  the  suggestions  of  the  National  Breast  Can- 
cer Coalition  and  put  advocates  who  are  representing  and  report  to 
consumer  groups  at  the  table  at  all  the  important  stages  on  the 
study  sections,  on  the  review  committees,  on  the  policy  setting 
boards.  I  think  they  also  need  to  make  a  commitment  that  is 
backed  up  by  policy,  by  systems,  by  procedures,  to  disclose  fully 
and  quickly  the  results  of  clinical  research,  whether  they're  good, 
bad,  or  embarrassing. 

I  think  if  the  NCI  demonstrates  a  willingness  to  take  these  steps 
instead  of  doing  as  it  appears  they've  been  doing  in  the  press  for 
the  past  few  weeks,  just  defending  themselves,  I  think  they  can  re- 
gain our  trust,  and  I  hope  that's  the  outcome. 

Mr.  Brown.  Ms.  Sigal,  can  they  regain  that  trust? 

Ms.  Sigal.  Well,  I'd  have  to  say  right  now  I'm  probably  one  of 
the  National  Cancer  Institute's  biggest  critics,  biggest  skeptics,  but 
I  agree  with  Ms.  Pearson.  I  think  it's  essential  to  regain  the  trust, 
and  as  I  said  in  my  statement,  it's  not  just  about  breast  cancer.  It 
could  be  a  study  about  heart  disease,  about  diabetes  or  AIDS,  but 
it's  essential  to  have  trust  and  credibility  in  the  National  Cancer 
Institute,  the  National  Institute  of  Health,  and  any  government 
sponsored  organizations.  So,  I  would  hope  that  could  be  re-estab- 
lished, but  I  think  it  needs  to  be  a  different  attitude  at  the  Na- 
tional Cancer  Institute,  and  hopefully  as  a  result  of  this  hearing 
and  Mr.  Chairman's  efforts,  that  maybe  the  National  Cancer  Insti- 
tute and  National  Institute  of  Health  and  the  efforts  of  the  sub- 
committee members,  maybe  they'll  understand  why  this  is  so  im- 
portant. Statistically  it  may  not  be  important  to  them,  but  it  sure 
is  important  to  me  and  to  thousands  of  others. 


38 

Mr.  Brown.  Ms.  Visco,  in  addition  to  a  change  of  attitude  at 
NCI,  what  steps  must  they  take  to  regain  the  trust  of  people  all 
over  the  country? 

Ms.  Visco.  Well,  I  echo  Ms.  Pearson's  support  of  the  National 
Breast  Cancer  Coalition's  demands,  including  consumer  advocates, 
but  I  want  to  add  something  to  that.  The  Coalition's  position  has 
been  from  the  time  we  heard  about  this  that  we  need  an  independ- 
ent investigation  and  an  independent  analysis  of  the  data.  We  were 
told  at  first  there  was  a  re-analysis.  Then  we  heard  that  there  real- 
ly wasn't  a  re-analysis  and  then  we're  not  certain  what  was  actu- 
ally analyzed  or  re-analyzed.  The  public  trust  has  eroded  com- 
pletely in  that  area,  and  we  do  need  an  independent  analysis  of 
what  happened.  I  think  that  would  go  a  long  way  toward  helping 
restore  trust. 

Mr.  Brown.  Ms.  Pearson,  what  went  wrong  at  Pittsburgh  in  the 
NCI  involving  the  Poisson  matter  and  the  refusals  and  delays  and 
re-analyzing  lumpectomy/mastectomy  data  after  the  fraud  at  St. 
Luc's?  What  actually  went  wrong? 

Ms.  Pearson.  Well,  I  have  to  just  tell  you  my  opinion,  and  I'm 
someone  who's  seen  Dr.  Fisher  in  action  at  a  few  meetings.  I've  had 
a  lot  of  interaction  with  NCI  officials.  As  you've  heard,  Dr.  Fisher 
was  hailed  as  an  important  key  researcher  in  women's  breast  can- 
cers for  many  years,  and  deservedly  so.  Our  founders,  in  fact,  and 
some  of  our  early  leaders  wrote  praises  of  him  in  books  designed 
for  the  lay  audience. 

I  believe  that  what  happened  over  the  80's  was  a  subtle  shift  in 
power,  to  the  point  where  Dr.  Fisher,  because  of  his  deserved  emi- 
nence and  respect  for  his  research,  began  to  be  more  important 
than  those  who  technically  funded  him  and  oversaw  him.  We  heard 
the  chairman  say  that  it  got  to  the  point  where  he  didn't  even  re- 
turn NCI's  phone  calls.  I  knew  he  wasn't  returning  mine,  and  that 
wasn't  a  real  big  surprise,  but  to  hear  that  he  wouldn't  return  Dr. 
Broder's  phone  calls  is  shocking  to  me. 

That's  what  I  think  happened,  but  somehow  the  NCI's  funding 
process  keeps  going  back  to  the  proven  producers.  Instead  of  hav- 
ing a  process  that  brings  in  new  blood,  fresh  ideas,  new  researchers 
who  will  have  to  be  accountable  to  those  who  fund  them,  they  rely 
too  much  upon  Dr.  Fisher's  proven  track  record  and  let  him  grow 
in  power  until  he  thought  he  didn't  need  to  be  accountable  to  them 
or  his  own  rules. 

Mr.  Brown.  What  are  other  scientists  and  researchers  saying 
about  what  you  just  said?  Are  they  echoing  that? 

Ms.  Pearson.  Most  of  the  conversations  I've  had  with  other  sci- 
entists and  researchers  are  very  casual  and  informal.  I  have  heard 
echos  of  that  kind  of  sense  of  what's  going  on,  that  Fisher  was  in 
a  way  untouchable. 

Mr.  Brown.  Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  time  of  the  gentleman  has  expired.  The  Chair 
is  under  the  discretion  that  by  the  rules,  the  Chair  is  now  going 
to  recognize  first  the  gentlewoman  from  Colorado  for  questions  and 
then  the  gentlewoman  from  Maine.  Ms.  Schroeder? 

Ms.  Schroeder.  Mr.  Chairman,  you  have  been  so  generous,  and 
we  really  thank  you  for  letting  the  co-chairs  be  here.  I  just  want 
to  be  very  brief  because  I  don't  want  to  take  the  time,  but  one  of 


39 

the  questions  I  have  for  NCI,  and  I  think  that's  what  you're  saying 
when  we  talk  about  trust,  is  they  seem  to  be  saying,  you  as  con- 
sumers and  you  as  people  who  are  trying  to  monitor  this,  are  really 
too  stupid  to  be  in  at  the  beginning  of  this  process  when  they  ask- 
ing the  questions,  framing  the  questions,  and  everything.  But  all 
of  a  sudden  you  became  very  bright  at  the  end  of  the  process.  When 
you  look  at  mammograms,  they're  saying  hey,  we  at  NCI  can't  real- 
ly decide.  We'll  just  have  women  sit  around  and  read  this  and  de- 
cide whether  or  not  they  need  it. 

So,  it's  amazing  how  bright  we  come  from  the  beginning.  They 
don't  want  us  playing  in  that  sandbox  when  they're  giving  out  the 
money  and  framing  the  questions  you  want  addressed  in  the  re- 
search and  monitoring.  Then  when  the  research  comes  out,  and  ob- 
viously they  haven't  been  monitoring  the  research  too  well,  they 
kind  of  say  gee,  we're  confused.  Now,  if  these  bright  scientists  who 
know  how  to  hand  out  the  money  become  very  confused  at  the  end 
and  don't  know  how  to  hand  out  the  recommendations,  we  got  a 
real  problem  with  attitude.  Am  I  hearing  you  right?  Would  trust 
help  if  you  could  get  in  at  the  beginning?  It's  a  little  confusing  to 
be  told  you're  so  bright  at  the  end  after  you've  been  shut  out  at 
every  single  level. 

Ms.  Visco.  Absolutely.  I  mean,  there's  no  question  that  would  go 
a  long  way,  and  probably  what  would  be  one  thing  that  would  go 
the  longest  way,  in  addition  to  this  type  of  hearing,  to  restoring 
public  confidence  is  letting  consumers  in  at  the  very  beginning  and 
giving  us  a  seat  at  the  table. 

Ms.  SCHROEDER.  That's  right,  and  I  think  that  goes  to  the  arro- 
gance that  we're  hearing.  I  know  I  think  of  myself  as  fairly  well 
informed,  but  I'm  really  rather  enraged  when  they  say  sit  down 
and  read  the  data  and  you  make  the  decision  whether  you  would 
need  a  mammogram  between  the  ages  of  40  and  50.  Please.  I 
mean,  are  we  all  to  go  back  to  medical  school,  or  what  are  we  sup- 
posed to  do?  That  doesn't  make  any  sense  to  me.  Cindy,  I  had  a 
specific  question  to  ask  you  that  you  may  or  may  not  want  to  an- 
swer, and  that's  on  the  tamoxifen  trial.  As  you  know,  there  are 
very  many,  many  healthy  women  enrolled  in  the  current  study.  As 
we  now  know  late,  one  of  the  side  effects  has  been  it  can  cause 
birth  defects. 

How  confident  are  you  that  this  trial,  the  women  in  this  trial,  the 
healthy  women  in  this  trial,  have  been  notified  of  that,  have  been 
told  to  get  birth  control,  or  are  there  hospitals  or  doctors  who  don't 
believe  in  birth  control  participating  that  may  not  tell  them  that 
part.  Have  you  looked  at  that,  because  another  thing  about  re- 
search is  getting  people  willing  to  be  in  the  research  things.  If  this 
type  of  thing  goes  on,  and  we'll  have  that  group  of  women  sitting 
at  the  table  saying  how  could  they  have  known  and  not  told  us  and 
gotten  consent  reforms,  and  we  don't  want  a  repeat  of  the  horror 
ofDES? 

Ms.  Pearson.  That's  right.  I'm  not  completely  confident  that  the 
11,000  healthy  women  who  enrolled  in  the  prevention  trial  before 
this — that  it's  in  right  now  have  been  adequately  informed  about 
the  risk  of  birth  defects  with  tamoxifen.  As  I  mentioned  briefly  in 
my  testimony.  Congressman  Ted  Weiss,  before  his  death,  conducted 
an  inquiry  into  the  quality  of  consent  that  was  being  given  to  par- 


40 

ticipants  in  the  trial.  His  staff  reviewed  268  forms  from  268  dif- 
ferent centers.  Twenty-six  percent  gave  inadequate  information 
about  the  need  to  use  birth  control  and  the  t3T)es  of  birth  control 
which  were  appropriate  to  be  used  in  the  context  of  this  study. 

Upon  questioning  at  the  hearing  that  was  chaired  by  Mr.  Payne, 
the  response  of  the  prevention  staff  was  well,  you  know,  some  of 
the  Catholic  hospitals  are  involved,  and  we  can't  tell  a  Catholic 
hospital  what  to  tell  women.  Now,  we  agree  100  percent.  Catholic 
hospitals  are  religious  institutions,  but  they  don't  have  the  right  to 
participate  in  a  trial  where  women's  safety  and  the  safety  of  un- 
born children  depends  on  their  knowledge  of  the  need  to  use  birth 
control  and  the  appropriate  kinds. 

Because  of  Dr.  Healy's  resistance  to  that  committee's  oversight, 
we  have  no  information  about  whether  or  not  those  26  percent  of 
the  participating  centers  have  fully  complied  with  the  need  to  give 
women  all  of  the  important  information. 

Ms.  SCHROEDER.  Mr.  Chairman,  that  may  be  something  we  may 
be  able  to  find  out  through  your  committee  because  if  that  is  still 
going  on,  I  would  say  stop  the  trial  immediately.  I  mean,  that's  out- 
rageous if  there  are  women  who  are  not  getting  the  full  consent, 
and  let's  hope  they  are. 

Thank  you  very  much,  and  I  thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentlewoman.  The  Chair  is 
going  to  have  the  staff  look  into  this  matter.  The  Chair  recognizes 
now  the  gentlewoman  from  Maine. 

Ms.  Snowe.  Thank  you,  Mr.  Chairman,  and  I  want  to  thank  all 
of  you  for  your  very  compelling  testimony,  and  Ms.  Sigal,  I  know 
we're  not  in  your  shoes,  but  we  certainly  share  your  agony.  In  lis- 
tening to  your  testimony,  I  couldn't  help  but  think  that  I  would  ap- 
proach the  issue  and  the  trauma  of  making  such  a  decision  just  the 
way  in  which  you  did,  based  on  information  that  my  doctor  would 
provide  and  asking  questions,  and  hopefully  getting  accurate  an- 
swers. I  just  truly  regret  that  this  has  happened.  We  just  want  you 
to  know  that  we  share  what  you  are  going  through. 

Ms.  Sigal.  Thank  you  very  much. 

Ms.  Snowe.  What  can  we  do  now,  immediately,  to  restore  con- 
fidence? I  know  we've  talked  about  placing  a  consumer  advocate, 
for  example,  at  the  table,  and  I  think  that's  a  very  important  issue, 
and  I  want  to  get  to  that  in  a  moment.  What  can  we  do  imme- 
diately to  restore  confidence,  because  I  am  concerned  about  what 
you're  going  through,  and  there  are  thousands  of  other  women  who 
are  going  through  the  same  crisis  right  now.  It's  a  crisis  of  con- 
fidence in  knowing  whether  or  not  you  made  the  right  decision. 
Would  it  be  an  independent  re-analysis  as  soon  as  possible? 

Ms.  Visco.  I  feel  that  would  be  a  very  strong  statement  to  the 
American  public.  If  the  National  Institutes  of  Health  and  the  Na- 
tional Cancer  Institute  recognized,  not  saying  they  are  incapable  of 
it,  but  recognizing  the  erosion  of  public  trust  and  because  of  that, 
stating  that  they  recognize  the  need  for  an  independent  analysis 
and  joining  with  this  committee  in  asking  for  and  in  making  that 
happen. 

Ms.  Snowe.  I  think  that  we  definitely  should  insist  on  it  because 
I  don't  think  there's  any  other  way  to  restore  the  confidence  on  this 
issue  given  the  series  of  terrible  errors  and  misjudgment  in  ethics. 


41 

I  think  we  have  an  obligation  to  do  that,  and  it's  something  that 
we  should  do.  Have  you  heard,  Ms.  Visco,  from  other  women  across 
the  country  as  a  result  of  this  study? 

Ms.  VisCO.  Yes.  We've  heard  from  quite  a  few  women  across  the 
country  as  a  result  of  this  study.  I  will  say  that  most  women  do 
recognize  the  existence  of  other  studies,  and  they  have  read  in  the 
papers  that  the  results  of  the  NSABP  study  will  not  change,  but 
they  are  still  concerned.  On  an  intellectual  level,  you  understand 
that.  On  an  emotional  level,  you  can't  accept  it. 

Ms.  Snowe.  Exactly. 

Ms.  VisCO.  And  that's  where  they  are. 

Ms.  Snowe.  And  that's  where  they  are.  So,  a  number  of  women 
are  aware  of  what  has  happened  based  on  press  accounts? 

Ms.  VisCO.  Oh,  absolutely. 

Ms.  Snowe.  And  obviously  the  only  way  they're  finding  that  out 
is  as  you  all  did  here. 

Ms.  Visco.  Right. 

Ms.  Snowe.  In  a  letter  to  the  co-chairs  of  the  caucus  from  NIH, 
it  talks  about  the  re-analysis  that  was  requested  of  Dr.  Fisher.  Is 
it  amazing  to  you  that  given  the  fact  that  they  already  knew  that 
there  was  a  serious  breach  of  ethics  and  falsification  of  data,  that 
they  would  go  back  to  the  individual  who's  responsible  for  conduct- 
ing this  clinical  study  trial  to  do  the  re-analysis,  and  just  to  as- 
sume that  it's  going  to  be  done.  Obviously  he  didn't  do  it.  They  re- 
quested— they  made  this  request  on  numerous  occasions,  and  obvi- 
ously he  ignored  their  request,  which  is  just  staggering  to  me  that 
somehow  the  NCI  had  no  ability  to  enforce  this  re-analysis  on  a 
timely  basis. 

Should  we  not  make  sure  that  there's  an  independent  coopera- 
tion any  time  that  there  is  a  problem  and  question  about  the  accu- 
racy of  the  data? 

Ms.  VisCO.  Yes,  absolutely,  I  agree,  especially  after  this  episode. 
Perhaps  if  this  episode  had  been  handled  differently,  we'd  have  a 
different  answer  to  that  question,  but  I  think  in  light  of  recent 
events,  absolutely  we'd  need  it,  as  part  of  the  process. 

Ms.  Snowe.  Because  I  am  just  amazed  that  Dr.  Fisher  would,  for 
whatever  reasons,  refuse  on  numerous  occasions — I  mean,  there 
were  so  many  time  lags  between  the  time  they  identified  the  dis- 
crepancies and  the  time  in  which  they  received  any  official  report, 
and  then  it  was  sort  of  tucking  this  all  into  the  Federal  Register 
in  a  very  brief  statement  in  hopes  that  no  one  is  going  to  identify 
it  or  catch  it.  I  mean,  that  was  obviously  the  intent  because  every- 
body knew  then  that  something  was  seriously  wrong  here  that  they 
wanted  to  go  unnoticed,  but  they  wanted  to  be  on  record  that  some- 
how they  had  identified  this  problem  and  they  made  public  recogni- 
tion of  that  problem. 

What  are  the  next  steps  that  we  should  take?  You  were  mention- 
ing having  an  advocate  in  the  process.  Recently,  I  co-signed  a  letter 
with  Representative  Towns  asking  for  a  consumer  advocate  on  the 
consensus  panel  for  ovarian  cancer.  Is  that  what  you're  talking 
about  as  well? 

Ms.  Visco.  Yes. 

Ms.  Snowe.  And  at  the  beginning  stages  of  the  process,  should 
that  be  by  statute  or  should  it  be  by  regulation? 


42 

Ms.  ViSCO.  I'm  not  certain  it  can  be  by  statute.  I  believe  it  should 
be  policy  of  the  National  Institutes  of  Health  and  the  National 
Cancer  Institute,  that  when  Federal  money  is  being  spent — we're 
working  on  getting  this  done  on  a  private  institutional  level  also, 
but  you  can  be  instrumental  in  helping  us  make  it  happen  on  a 
public  level,  that  consumer  representation  belongs  at  the  table 
study  sections,  data  monitoring  committees,  oversight  committees, 
not  just  advisory  boards. 

Ms.  Snowe.  Well,  the  reason  why  I  asked  whether  it  should  be 
done  by  regulation  or  statute  is  because  we  had  a  problem  with  the 
fact  that  women  were  excluded  systematically  from  clinical  study 
trials,  and  actually,  NIH  was  violating  its  own  policy.  It  was  not 
enforcing  its  own  policy.  So,  I  have  mixed  feelings  about  whether 
or  not  that  should  be  done  by  regulation  or  statute  so  that  we  have 
the  assurance  that  it  is  being  done  and  that  we  don't  have  to  go 
through  the  process  of  determining  whether  or  not  it's  being  en- 
forced or  not,  that  we  know  by  statute  they  are  required,  and  obvi- 
ously we  understand  that  there  could  be  problems  there,  too,  but 
it's  obviously  going  to  be  much  harder  for  them  to  contravene  pub- 
lic law. 

Mr.  Brown.  Absolutely.  When  you're  handing  out  money  on  a 
Congressional  level  and  on  a  National  Cancer  Institute  level,  you 
certainly  have  the  power  to  make  as  a  condition  to  being  eligible 
for  that  money,  the  fact  that  a  consumer  representative  must  be  in- 
volved. 

Ms.  Snowe.  Well,  thank  you  all  very  much. 

Mr.  DiNGELL.  The  time  of  the  gentlewoman  has  concluded.  The 
Chair  would  like  to  express  my  personal  thanks  to  each  of  you  for 
your  valuable  assistance  to  the  committee.  Your  help  has  been  of 
great  importance  to  us  in  developing  our  record.  The  Chair  advises 
that  the  questions  that  you  have  raised,  including  the  chronology 
of  events,  will  be  brought  to  the  attention  of  witnesses  from  the 
NIH.  The  Chair  excuses  the  panel  members  with  our  gratitude.  We 
also  wish  you,  Ms.  Sigal,  great  good  fortune. 

Ms.  Sigal.  Thank  you  very  much,  Mr.  Chairman. 

Mr.  DiNGELL.  And  you  also,  Ms.  Visco.  I  want  to  extend  in  addi- 
tion to  that  my  personal  thanks.  Thank  you  very  much,  ladies. 

Ms.  SiGAL.  Thank  you,  and  thank  you,  Mr.  Schaefer. 

Mr.  DiNGELL.  The  Chair  announces  the  next  panel.  The  panel 
will  be  composed  of  Dr.  Harold  Varmus,  Director  of  the  National 
Institutes  of  Health,  and  Dr.  Samuel  Broder,  Director,  National 
Cancer  Institute.  They  will  be  accompanied  by  Dr.  Bruce  Chabner, 
Director,  Division  of  Cancer  Treatment,  Dr.  Michael  A.  Friedman, 
Associate  Director,  Cancer  Therapy  Evaluation  Program,  and  Dr. 
Lyle  W.  Bivens,  Director,  Office  of  Research  Integrity.  Gentlemen, 
thank  you  for  being  with  us  today.  We  express  the  thanks  of  the 
committee  to  you  for  your  presence.  The  Chair  advises  that,  as  you 
know,  the  practices  of  the  committee  are  that  all  witnesses  who 
testify  before  the  committee  testify  under  oath.  Gentlemen,  do  any 
of  you  have  any  objection  to  testifying  under  oath?  Very  well,  the 
Chair  advises  that  if  you  do  testify  under  oath,  it  is  of  course  your 
right  to  be  advised  by  counsel  in  the  course  of  your  appearance.  Do 
any  of  you  desire  to  be  advised  by  counsel  as  you  testify  under 
oath? 


43 

[No  response.] 

Mr.  DiNGELL.  Very  well.  The  Chair  advises  that  copies  of  the 
rules  of  the  subcommittee,  rules  of  the  committee,  rules  of  the 
House  are  there  at  the  witness  table  before  you  in  the  red  and  blue 
books  to  inform  you  of  your  rights  and  limitations  on  the  power  of 
the  committee  as  you  testify  before  us  today.  Grentlemen,  if  you 
have  no  objection  then  to  testifying  under  oath,  would  you  please 
each  rise  and  raise  your  right  hand? 

[Panel  sworn.] 

Mr.  DiNGELL.  Gentlemen,  you  can  consider  yourselves  to  be 
under  oath.  Gentlemen,  we  will  recognize  you  beginning  with  Dr. 
Varmus,  then  Dr.  Broder,  and  then  by  Dr.  Bivens,  and  then  by  the 
others  as  you  might  find  it  necessary  or  might  suit  the  needs  of  the 
hearing.  Doctor,  you  are  recognized. 

TESTIMONY  OF  HAROLD  VARMUS,  DIRECTOR,  NATIONAL  IN- 
STITUTES OF  HEALTH;  SAMUEL  BRODER,  DIRECTOR,  NA- 
TIONAL CANCER  INSTITUTE,  ACCOMPANIED  BY  BRUCE 
CHABNER,  DIRECTOR,  DIVISION  OF  CANCER  TREATMENT, 
MICHAEL  A.  FRIEDMAN,  ASSOCIATE  DIRECTOR,  CANCER 
THERAPY  EVALUATION  PROGRAM;  AND  LYLE  W.  BIVENS,  DI- 
RECTOR, OFFICE  OF  RESEARCH  INTEGRITY,  DEPARTMENT 
OF  HEALTH  AND  HUMAN  SERVICES 

Mr.  Varmus.  Mr.  Chairman,  thank  you.  Before  I  proceed  with 
my  prepared  statement,  I  would  like  to  say  a  word  or  two  about 
the  transition  in  mood  that  will  accompany  the  development  of  this 
panel.  We've  just  experienced  an  emotionally  trying  discussion  by 
three  women  who  have  all  been  affected  by  or  are  involved  in  the 
ramifications  of  the  breast  cancer  studies  that  we've  talked  about. 
Ms.  Sigal's  testimony  was  particularly  impassioned  and  moving. 
We're  going  to  now  move  into  a  more  analytic  mode  to  discuss  the 
process  by  which  the  current  events  unfolded. 

As  we  do  that,  I  think  it's  important  to  realize  that  although  we 
are  five  men  at  this  table  responsible  for  some  of  the  events  that 
we  want  to  explore  and  for  their  oversight,  it's  important  to  re- 
member that  we,  too,  have  a  deep,  passionate  involvement  in  these 
issues.  In  my  own  case,  my  mother  and  my  grandmother  died  of 
breast  cancer.  I've  devoted  most  of  my  research  career  to  the  pur- 
suit of  an  understanding  of  breast  cancer.  I  have  dear  friends  who 
are  making  the  kinds  of  decisions  Ms.  Sigal  and  Ms.  Viscoe  were 
describing.  I  feel  a  deep  responsibility  for  the  research  that  leads 
to  the  ability  of  women  and  their  physicians  to  make  such  deci- 
sions. 

We  have  to  recognize  as  well  that  as  the  previous  panel  indi- 
cated, we're  talking  not  just  about  gender  issues  and  breast  cancer, 
we're  talking  about  all  of  the  research  that's  affected  by  NIH.  We're 
talking  about  events  that  could  have  affected  a  study  of  prostate 
cancer  or  lung  cancer  or  other  diseases  that  are  rare  or  common. 
We  take  these  responsibilities  very  seriously,  and  as  we  engage  in 
this  discussion  and  proceed  to  a  detailed  analysis  of  how  we've  re- 
sponded to  the  events  that  you've  heard  described,  that  although 
we  analyze  these,  the  passion  that  you've  heard  in  the  previous 
panel  is  shared  my  many  of  us. 


44 

That  being  said,  Mr.  Chairman,  we  welcome  the  chance  to  ap- 
pear before  you  today  to  discuss  the  disturbing  events  that  have 
been  well  described  here  in  the  previous  panel  and  by  yourself  and 
in  the  press  that  involve  the  clinical  studies  of  breast  cancer  car- 
ried out  over  many  years  by  the  NSABP  under  the  sponsorship  of 
the  NCI.  Before  I  introduce  Dr.  Broder,  the  Director  of  the  NCI, 
who  will  provide  a  detailed  account  of  these  events  and  his  efforts 
to  respond  to  them,  and  before  we  introduce  his  colleagues  and 
Lyle  Bivens  from  the  Office  of  Research  Integrity,  I  would  like  to 
outline  what  I  hope  we  can  accomplish  during  this  panel. 

First  and  foremost,  we  can  reassure  women,  including  Ms.  Sigal, 
who  have  chosen  breast  sparing  surgery  for  breast  cancer,  that 
they  have  made  a  decision  that  is  strongly  and  unequivocally  sup- 
ported by  current  scientific  evidence,  evidence  provided  by  both  the 
NSABP  and  by  many  other  groups.  That  analysis  has  been  inde- 
pendently analyzed  by  the  EMMES  Corporation,  as  Dr.  Broder  will 
review.  We  are  prepared  to  submit  all  the  data  to  independent  au- 
diting if  that  proves  to  be  necessary. 

Second,  we  can  summarize  the  central  facts  in  a  complex  story 
that  includes  a  long  history  of  path  breaking  clinical  science  by  the 
NSABP,  leading  to  many  of  the  improvements  in  the  treatment  of 
this  disease,  which  regrettably  we  still  incompletely  understand.  It 
also  includes  a  well  documented  episode  of  flagrant  fraud  that 
you've  heard  discussed  at  one  of  its  more  than  400  participating  in- 
stitutions, and  the  facts  include  inadequate  and  slow  administra- 
tive responses  and  insufficient  auditing  procedures  by  arms  of  the 
government  and  by  the  NSABP. 

Third,  we  hope  we  can  describe  corrective  measures  that  have 
been  taken  in  recent  weeks  by  the  NCI  to  improve  the  administra- 
tive functions  of  the  NSABP  and  to  strengthen  oversight  by  the 
NCI.  Such  measures  should  increase  the  likelihood  that  fraudulent 
acts  occurring  in  the  conduct  of  clinical  studies  will  be  promptly  de- 
tected and  reported  in  the  future.  In  this  way,  we  believe  that  the 
lessons  learned  from  the  current  incident  can  enhance  the  conduct 
of  medical  science  supported  by  the  NCI  and  by  the  other  compo- 
nents of  the  NIH. 

It's  important  to  recognize  at  the  outset  that  remarkable 
progress  has  been  achieved  in  the  practice  of  medicine  and  surgery 
in  the  past  few  decades.  Consider  just  three  prominent  examples: 
The  cure  of  acute  leukemia  in  children  by  chemotherapy,  the  reduc- 
tion in  mortality  by  control  of  high  blood  pressure,  the  prevention 
of  blindness  by  laser  surgery  in  diabetic  patients.  In  each  of  these 
three  instances  and  in  many  other  examples,  including  the  breast 
cancer  therapies  under  discussion  today,  progress  can  be  attributed 
to  the  formation  of  large  cooperative,  multi-institutional  and  often 
multinational  groups. 

The  well  documented  successors  of  such  groups  require  meticu- 
lous planning,  coordination,  and  oversight  to  insure  that  protocols 
are  uniformly  followed  in  an  often  varied  and  far  flung  group  of  in- 
stitutions. Occasionally,  as  in  the  case  of  the  NSABP,  such  proce- 
dures may  fail,  and  the  malfeasance  of  an  investigator  may  go  un- 
detected and  uncorrected.  The  hard-earned  prestige  of  productive 
groups  such  as  the  NSABP  may  even  be  among  the  factors  that 
contribute  to  the  deficiencies  of  monitoring  and  reporting. 


45 

Our  discussion  today  will  properly  focus  not  on  the  act  of  fraud 
itself  but  on  the  methods  for  detecting,  investigating  and  publiciz- 
ing fraud  and  for  evaluating  its  consequences.  The  questions  we 
will  address  are  especially  contentious  and  complex  when  the  sus- 
pected fraud  might  affect  the  outcome  of  clinical  studies  and  hence 
might  alter  the  procedures  used  in  medical  practice.  Under  such 
circumstances,  there  are  profound  tensions  between  the  public's 
need  for  access  to  information  that  could  affect  people's  health  and 
the  right  of  someone  accused  of  fraud  to  be  protected  by  due  proc- 
ess. 

The  public  does  not  want  to  be  frightened  by  false  accusations. 
Likewise,  the  public  does  not  want  to  be  deprived  of  knowing  the 
consequences  of  accurate  ones.  For  these  reasons  and  others,  as  the 
previous  panel  has  stressed,  the  prompt  resolution  of  allegations  of 
fraud  and  the  rapid  dissemination  of  findings  of  fraud  in  clinical 
research  are  matters  of  great  importance  to  us,  and  they  deserve 
our  attention  today  and  in  the  future. 

It's  my  hope  that  this  hearing  can  provide  an  opportunity  to  un- 
derstand what  has  happened  in  the  current  instance  and  to  ac- 
knowledge the  dedication  and  integrity  of  the  vast  majority  of  clini- 
cal researchers  whose  valuable  efforts  may  be  jeopardized  by  the 
recent  events.  It's  an  opportunity,  most  importantly,  to  reflect  upon 
ways  we  could  learn  from  this  experience  to  improve  what  we  do 
to  advance  the  Nation's  health  and  to  insure  that  patients  such  as 
those  you've  heard  in  the  first  panel  receive  the  benefits  of  our  ef- 
forts as  caretakers  of  the  Nation's  health. 

At  this  point,  Mr.  Chairman,  I'd  like  to  introduce  Dr.  Sam 
Broder,  the  Director  of  the  NCI,  who  will  give  you  an  account  of 
his  institution's  response  to  these  events. 

STATEMENT  OF  SAMUEL  BRODER 

Mr.  Broder.  Good  morning,  Mr.  Chairman.  Good  morning, 
Madam  Chairwoman  and  members  of  the  subcommittee.  I  am  Dr. 
Samuel  Broder,  Director  of  the  National  Cancer  Institute,  the  NCI. 
Accompanying  me  today  on  your  left  are  Dr.  Bruce  Chabner,  Direc- 
tor of  the  Division  of  Cancer  Treatment  of  the  National  Cancer  In- 
stitute and  Dr.  Mike  Friedman,  the  Associate  Director  of  the  Can- 
cer Therapy  Evaluation  Program.  We  are  very  pleased  to  have  this 
opportunity  to  follow  up  on  Dr.  Varmus's  remarks. 

I  would  like  to  discuss  NCI's  recent  actions  following  the  Office 
of  Research  Integrity  findings  by  fraud  on  the  part  of  a  surgeon  at 
L'opital  St.  Luc  in  Montreal,  and  the  steps  taken  by  NCI  to  correct 
this  situation.  The  oversight  and  monitoring  of  clinical  trials  is 
vital  to  insure  that  research  advances  are  based  on  sound  and  ac- 
curate data.  Honest  errors  can  and  do  occur,  and  will  always  occur 
whenever  human  beings  are  involved  in  any  process.  However, 
fraud  is  different  and  cannot  be  tolerated.  We  have  a  responsibility 
to  all  cancer  patients,  physicians,  and  scientists  to  validate  the  in- 
tegrity of  our  clinical  research. 

There  is  in  this  country  widespread  use  of  breast  sparing  proce- 
dures as  an  alternative  to  mastectomy.  I  am  not  that  old,  or  I  don't 
think  I'm  that  old,  but  within  my  medical  school  training,  there 
was  an  era  in  which  women  would  be  informed  that  they  had  a 
biopsiable  lesion,  would  be  given  a  general  anesthetic,  would  have 


46 

no  option  except  to  go  under  the  surgery,  and  to  not  know  whether 
they  would  awake  with  a  benign  biopsy  or  what  was  then  a  radical 
mastectomy.  A  medical  student  in  my  era  who  challenged  this 
practice  of  medicine  in  that  time  would  possibly  face  problems  with 
his  or  her  career  development. 

Today,  I  assure  you,  Mr.  Chairman,  members  of  the  subcommit- 
tee, the  general  public,  and  physicians,  that  breast  sparing  surgery 
remains  an  appropriate  and  safe  procedure.  I  do  not  come  here  be- 
fore you  as  merely  a  scientist  or  government  administrator  per  se, 
but  as  someone  who  knows  how  breast  cancer  can  devastate 
women  and  entire  families  at  first  hand.  No  woman  who  has  relied 
on  the  results  of  modem  clinical  trials  to  select  a  breast  sparing 
procedure  following  a  diagnosis  of  invasive  breast  cancer  should 
feel  that  she  has  made  the  wrong  choice  based  on  the  topics  under 
discussion  today. 

The  principal  of  breast  sparing  surgery  is  based  on  a  set  of  at 
least  six  international  studies  and  a  couple  that  are  not  yet  pub- 
lished, which  provide  the  clear  basis  for  current  medical  practice. 
The  issue  of  ipsilateral  breast  cancer  that  we've  heard,  that  is  a  re- 
currence in  the  same  breast,  may,  as  the  facts  were  presented  in 
earlier  testimony,  may  possibly  be  Dr.  Fisher's  view,  but  I  wish  to 
assure  the  committee  that  it  is  more  assuredly  not  my  view,  and 
I  believe  I  have  made  that  point  clear  to  the  staffers  who  have  been 
kind  enough  to  speak  to  me  on  this  point.  We  certainly  consider 
ipsilateral  breast  cancer  recurrence  to  be  a  valid  indicator  of  the 
process,  and  in  fact,  lumpectomy  and  radiation  compares  quite  fa- 
vorably in  this  connection  to  other  available  therapeutic  ap- 
proaches. 

Before  discussing  the  details  of  this  case,  Mr.  Chairman,  I  be- 
lieve that  documents  summarizing  the  NCI's  own  statistical  analy- 
sis done  through  a  contractor  who  is  an  agent  of  the  National  Can- 
cer Institute,  that  those  documents  dealing  with  breast  sparing 
surgery  and  other  treatment  approaches  have  been  provided  to  the 
committee,  and  we  are  also  making  these  reports,  the  reports  that 
pull  out  the  St.  Luc's  data  widely  available,  employing  computer 
networks  that  will  make  the  results  as  widely  available  as  possible. 

In  addition,  perhaps  it  is  of  some  interest  to  the  committee  that 
we  had  outside  reviewers  and  tried  to  involve  statistical  experts 
with  a  known  consumer  advocacy  position.  Dr.  Kay  Dickerson  has 
reviewed  the  NCI  reports  of  the  statistics  excluding  the  fraudulent 
data,  and  she  writes,  and  I'm  quoting,  "The  ansdyses  were  clearly 
presented,  and  seemed  to  be  properly  done." 

Before  discussing  the  details  of  this  case,  perhaps  I  could  briefly 
comment  on  the  NSABP.  The  group  has  existed  for  over  35  years 
as  a  leading  clinical  trials  component  in  the  breast  cancer  field.  It 
consists  of  several  thousand  doctors  at  more  than  400  sites  and  is 
one  of  9  clinical  trials  cooperative  groups  that  conduct  large  scale 
clinical  studies  supported  by  the  National  Cancer  Institute  in  the 
United  States  and  Canada.  The  NSABP's  founder.  Dr.  Bernard 
Fisher,  constructed  the  group  as  a  broad  based  organization  of  com- 
munity and  academic  surgical  oncologists  whose  findings  would  re- 
flect the  ability,  the  capabilities  and  the  imperfections  of  practicing 
physicians  in  the  real  world  to  employ  innovative  therapies.  The 
NSABP  has  pioneered  and  established  many  principles  of  breast 


47 

cancer  treatment  that  have,  in  fact,  been  repUcated  by  other  orga- 
nizations and  groups. 

Please  let  me  say  something  that  I  hope  is  not  misunderstood  in 
testimony  before  this  committee.  Today,  Dr.  Fisher's  prior  record  of 
scientific  preeminence,  indeed  even  the  fact  that  he  as  a  surgeon 
played  a  special  role  in  liberating  women  from  having  to  undergo 
mastectomies,  all  of  this  is  irrelevant  to  reviewing  what  went 
wrong  and  how  we  should  do  better. 

In  June  1990,  the  NSABP  staff  detected  inconsistent  data  in  the 
record  of  a  patient  previously  entered  on  an  NSABP  trial  in  Mon- 
treal. This  was  at  L'opital  St.  Luc.  In  two  site  visits  of  the  ensuing 
7  months,  NSABP  became  convinced  that  fraud  had  taken  place, 
and  in  February  1991,  notified  the  NCI  for  the  first  time.  The  NCI 
notified  the  Office  of  Scientific  Integrity,  the  precursor  of  the  Office 
of  Research  Integrity,  which  will  be  represented  by  my  colleague. 
Dr.  Lyle  Bevins,  and  also  notified  the  Food  and  Drug  Administra- 
tion and  the  Office  of  Protection  from  Research  Risks. 

Government  audits  were  organized  and  carried  out,  and  they 
quickly  confirmed  the  findings  of  fraud.  To  be  candid,  this  was  not 
a  difficult  investigation  from  my  point  of  view.  The  investigator, 
Dr.  Roger  Poisson,  admitted  the  forgery  and  falsification  of  dates 
and  other  fabrications  in  the  records  of  a  small  number  of  patients 
that  he  entered  into  NCAB.  I  use  the  small  number  as  his  point 
of  view,  not  my  point  of  view.  His  later  justifications  for  these  acts 
are  incomprehensible  to  us.  They  remain  incomprehensible  to  us  to 
this  day. 

OSI — now  ORI — undertook  a  detailed  investigation.  During  such 
an  investigation,  ORI  generally  prefers  to  have  an  embargo  on  pub- 
lic discussions  and  disclosures.  However,  Dr.  Fisher  was  asked  by 
both  NCI  and  ORI,  orally  and  in  writing,  to  perform  a  re-analysis 
and  prepare  a  publication  of  the  trials  affected  by  the  fraud.  It  is 
my  personal  view  that  had  he  listened  to  us  or  had  we  been  able 
to  force  him  to  listen  to  us,  this  hearing  would  be  unnecessary.  As 
early  as  July,  1991,  an  SABP  assured  NCI  staff  that  outcomes  were 
unchanged.  In  March,  1992,  Dr.  Fisher  presented  his  re-analyzed 
data  to  medical  and  statistical  of  OSI,  NCI  and  NIH  at  a  presen- 
tation in  Bethesda,  and  concluded  there  were  no  changes  in  the 
major  end  points  of  the  affected  studies. 

NSABP  was  asked  to  prepare  a  manuscript  to  publish  their  re- 
analysis  at  the  conclusion  of  the  misconduct  investigation.  Neither 
I  nor  NCI  felt  there  were  any  urgent  public  health  hazards  or 
changes  in  medical  practice  that  would  warrant  breaking  the  em- 
bargo which  ended  in  April,  1993  with  the  release  of  the  final  ORI 
report.  We  are  re-assessing  the  algorithm  by  which  we  decide 
whether  an  embargo  needs  to  be  broken,  and  this  particular  kind 
of  faith  to  an  embargo  or  an  adherence  to  an  embargo  is  unlikely 
to  ever  be  repeated,  at  least  from  my  point  of  vie\/. 

The  report's  findings  of  fraud  were  summarized  in  a  number  of 
formats  which  are  not  satisfactory  and  include,  of  course,  the  NIH 
guide  in  June  of  1993.  Each  issue  of  the  guide  is  mailed  to  over 
36,000  subscribers  and  is  available  on  computer  networks,  but 
there  can  be  no  doubt  that  ORI  and  NCI  put  Dr.  Fisher  on  notice 
to  publish  a  re-analysis.  It  is  clear,  however,  that  the  methods  used 
to  announce  the  results  of  this  misconduct  were  not  adequate,  and 


48 

we  will  approach  the  dissemination  of  such  results  working  closely 
with  ORI  in  a  more  active  and  visible  way  in  the  future. 

In  February  1994,  the  NSABP  sent  NCI  a  written  summary  of 
their  re-analysis  of  clinical  trials,  including  the  breast  sparing  pro- 
cedure study.  Shortly  thereafter  in  March  of  1994,  accounts  in  the 
media  generated  concerns  about  the  delays  in  publication  and 
raised  the  possibility  that  the  practice  of  medicine  might  be  based 
on  faulty  conclusions.  I  believe  it  is  Dr.  Fisher's  assertion  or  the  as- 
sertion of  his  staff  that  he  was  preparing  to  publicize  these  results 
in  June  of  1994. 

There  is  cause  for  reflection  and  review  of  actions  regarding  what 
the  NCAB  and  NCI  did  in  responding  to  these  issues.  First,  let  us 
look  at  NSABP.  The  NSABP  failed  to  publish  its  re-analysis,  in- 
form its  membership  of  the  incident,  reassure  the  public,  notify  sci- 
entific journal  editors  and  other  grant  supported  organizations  of 
the  fabrication,  public  accurate  papers  that  clearly  disclose  what 
Dr.  Poisson  did,  and  in  a  larger  sense,  adhere  to  NCI's  guidelines 
for  management  of  the  group's  operation  office  and  quality  assur- 
ance functions.  The  NSABP  did  not  respond  to  constructive  criti- 
cism by  NCI  staff. 

Unfortunately,  the  problems  of  the  NSABP  have  continued.  In  an 
NCI  on  site  review  of  their  operations  in  Pittsburgh  toward  the  end 
of  March  of  1994,  NCI  staff  found  additional  evidence  of  deficient 
auditing  and  reporting  practices.  The  staff  found  that  the  NSABP 
had  failed  to  conduct  required  audits  of  its  treatment  studies  in  a 
timely  fashion  and  had  failed  to  transmit  to  NCI  reports  of  certain 
audits  of  its  treatment  and  prevention  trials  as  required. 

In  the  files,  we  found  a  report  of  an  additional  episode  of  possible 
data  manipulation  involving  a  patient  on  a  different  study  at  yet 
a  different  hospital  in  Montreal.  This  finding  was  initially  discov- 
ered by  the  NSABP  in  September  of  1993  but  had  not  been  re- 
ported to  NCI  and  was,  as  far  as  we  can  tell,  being  handled  as  a 
routine  matter  subject  to  an  additional  follow-up  site  visit.  The  NCI 
staff  initiated  an  emergency  site  visit  to  the  new  institution  in 
question,  confirmed  a  suspicious  alteration  in  an  X-ray  report,  and 
immediately  notified  ORI,  which  is  now  investigating  the  matter. 

That  latest  irregularity  appears  to  involve  a  clinical  study,  the 
tamoxifen  breast  cancer  prevention  trial  that  is  not  completed  and 
therefore  is  unpublished.  I  have  been  informed  by  ORI  that  the 
breast  cancer  treatment  results  were  not  tainted  or  do  not  appear 
to  be  tainted  by  this  latest  irregularity  in  Montreal. 

The  NSABP  had  no  explanation  for  its  failure  to  comply  with  re- 
quests to  update  and  report  its  audit  findings  nor  for  its  delay  in 
informing  its  membership  of  these  problems  and  promptly  submit- 
ting its  re-analysis  for  publication.  We  believe  that  the  primary  re- 
sponsibility for  correcting  fraudulent  work  in  the  literature  lies 
with  clinician  authors  of  the  original  publication.  However,  as  I 
mentioned  earlier,  the  NCI  clearly  has  responsibilities  as  well. 

Now,  let  us  look  at  NCI.  Despite  the  requests  by  NCI  and  ORI 
for  the  group  to  re-analyze  and  publish  the  data  and  to  bring  oper- 
ations into  compliance,  we  failed  to  compel  these  actions  forcefully 
and  in  a  timely  way.  We  also  did  not  adequately  overcome  our  re- 
luctance to  demand  that  an  independent  investigator,  who  himself 
was  not  a  respondent  in  a  misconduct  case,  turn  over  his  data  files 


49 

in  their  entirety  to  have  other  re-analyze  the  results.  We  are  trying 
to  learn  from  this  experience  to  ensure  that  our  response  of  epi- 
sodes of  fraud  in  clinical  trials  is  prompt  and  effective.  Thus,  re- 
cently NCI  personnel  have  taken  possession  of  the  computer  data 
files,  analyzed  and  disseminated  the  results,  initiated  a  govern- 
ment run,  on-  site  audit  of  clinical  research  conducted  by  the  group 
and  certain  other  groups. 

In  addition,  in  doing  so,  NCI  has  clearly  confirmed  the  principle 
that  the  granting  agency  can  and  will  demand,  distribute  and  dis- 
close a  grantee's  data  in  response  to  pressing  public  health  needs. 
Fraud  will  by  definition  always  constitute  such  a  need.  We  will  not 
tolerate  explanations  that  the  data  belonged  to  the  grantee.  We 
will  never  again  hesitate  to  exercise  this  authority  whenever  nec- 
essary. 

Our  staff  also  failed  to  mobilize  after  warning  signs  of  delay  in 
clearing  up  the  scientific  literature  and  repairing  inadequate  com- 
pliance with  auditing  requirements.  This  may  have  occurred  be- 
cause of  several  factors  taken  alone  or  in  combination,  which  I  be- 
lieve the  committee  will  wish  to  note,  and  these  may  be:  NSABP's 
proud  reputation;  the  visible  status  of  Dr.  Fisher  in  the  scientific 
community  and  also  as  a  member  of  our  presidentially  appointed 
National  Cancer  Advisory  Board;  a  self-consciousness  in  asserting 
authority  over  an  independent  researcher;  or  a  mistaken  belief  that 
somehow  the  lapses  by  a  senior  research  group  were  temporary. 
We  are  very  sorry  that  this  happened,  and  we  assure  you  that  such 
errors  will  not  happen  again.  We  have  created  a  new  unit,  the  Clin- 
ical Trials  Monitoring  Branch,  to  monitor  compliance  in  our  cooper- 
ative groups,  which  will  implement  our  rules  without  fear  or  favor. 
We  will  take  swift  and  uninhibited  action  in  the  event  of  a  lack  of 
compliance.  A  prior  record  of  accomplishments  of  any  level  will  not 
be  used  as  a  defense  against  adhering  to  our  regulations.  New  pro- 
cedures are  in  place  to  report  and  track  audits,  and  we  are  initiat- 
ing a  system  of  NCI-directed  site  visits  to  validate  the  cooperative 
group  audit  findings  with  sites  selected  at  random. 

Also,  we  are  reviewing  our  computer  security  and  password-only 
entry  procedures  for  the  various  clinical  trials  in  which  a  central 
laboratory  runs  lab  tests  on  auto  analyzers  with  transfers  to  a  com- 
puter database  in  order  to  avoid  the  possibility  of  the  scientific  mis- 
conduct through  a  computer  hacker  could  affect  centralized  com- 
puter operations,  and  we  want  to  address  this  issue. 

We  are  developing  a  new  internal  NCI  operations  manual  for  sit- 
uations involving  fraud  and  scientific  misconduct.  This  manual  will 
be  in  place  within  days.  The  messages  also  include  automatic  noti- 
fication of  journals  where  falsified  data  had  been  publish,  and  in 
forming  other  financial  sponsors  of  projects  affected  by  scientific 
misconduct.  Any  administrator  at  the  NCI  can  initiate  an  auto- 
matic series  of  steps  with  checklists,  enabling  NCI  as  a  whole  to 
act  decisively  and  resolutely  while  at  the  same  time  protecting  the 
legitimate  interests  of  all  parties.  These  measures  will  protect  the 
public  health  and  provide  for  the  recovery  of  Federal  funds.  The 
new  branch  has  begin  to  review  policies  and  procedures  for  mon- 
itoring trials  and  plans  to  revise  and  amplify  the  guidelines  for 
every  aspect  of  the  process.  Dr.  Michelle  Christian,  who  is  the  act- 
ing chief  of  this  new  branch,  is  in  the  hearing  room  today. 


50 

A  number  of  new  policies  are  in  force.  All  site  visits  will  include 
an  individual  from  outside  the  cooperative  group  conducting  the 
audit.  All  audits  will  be  on  site.  In  addition  to  any  other  regular 
audit  and  oversight  procedures,  the  NCI,  using  Federal  employees 
and  its  own  contractors,  will  conduct  special  audits  of  cooperative 
groups,  sites  selected  at  random,  to  verify  the  accuracy  of  coopera- 
tive group  audits.  This  will  impose  an  external  element  of  unpre- 
dictability and  surprise  in  the  auditing  and  oversight  functions. 

Accrual  of  new  patients  will  automatically  be  suspended  for  insti- 
tutions that  have  not  had  a  site  visit  with  regular  3  year  cycles. 
Audit  schedules  and  reports  will  be  computerized.  The  NCI  is  ex- 
ploring a  common  on-line  computer  system  to  be  shared  by  the 
groups.  The  peer  review  site  visit  process  will  be  used  not  only  for 
scientific  review,  but  also  to  help  identify  problems  in  protocol  com- 
pliance and  quality  assurance. 

The  branch  will  issue  a  quarterly  report  to  the  Executive  Com- 
mittee of  the  NCI  and  the  NCI  components  that  are  doing  clinical 
trials.  Grantees  that  fail  to  meet  our  requirements  for  accuracy,  re- 
liability and  time  limits  will  be  suspended. 

We  appreciate  the  need  to  improve  the  flow  of  information  on 
drug  toxicities  between  NCI  and  the  cooperative  groups.  The  early 
detection  of  side  effects  poses  special  challenges  in  large  commu- 
nity-based clinical  trials.  As  a  general  rule,  in  the  future,  we  will 
try  to  have  the  National  Cancer  Institute  in  effect  actually  hold  the 
investigation  of  a  new  drug  application,  what  is  called  the  INDA, 
for  studies  that  we  sponsor. 

Except  under  compelling  circumstances,  I  must  tell  you  candidly 
that  this  is  not  always  an  investigator's  or  a  pharmaceutical  com- 
pany's first  choice.  But  holding  the  INDA  enhances  certain  types 
of  reporting  and  additional  oversight  issues  beyond  grand  manage- 
ment and  larger  clinical  trials.  For  example,  in  the  tamoxifen  ran- 
domized trials,  NCI  did  not  hold  the  IND,  and  therefore  would  not 
necessarily  have  been  the  very  first  in  line  to  receive  data  on  new 
cases  of  endometrial  cancer  or  other  potential  complications  from 
tamoxifen.  We  will  try  to  communicate  in  novel  ways  directly  with 

Eatients  on  clinical  trials.  For  example,  we  will  tests  on  a  pilot 
asis  an  electronic  patient  information  bulletin  board  to  provide  pa- 
tients with  the  latest  communications  specific  to  a  given  trial.  This 
is  to  supplement,  not  replace,  our  other  ways  of  communicating 
with  patients  and  consumers,  including  our  cancer  information 
service,  cancer  facts,  and  physician  data  query  systems. 

What  about  the  current  status  of  the  NSABP?  The  NSABP  is  an 
important  resource  for  conducting  large  scale  randomized  clinical 
trials  in  this  country.  A  number  of  changes  have  now  been  made 
to  strengthen  the  operation  of  NSABP.  The  NCI  instructed  the 
granting  institution  to  change  the  principal  investigator,  and  Dr. 
Fisher,  the  leader  of  the  group  since  its  inception,  has  stepped 
aside.  I  do  not  recall  a  similar  request  ever  having  been  made  with- 
in my  historical  knowledge  of  tne  NCI  on  a  major  figure  of  Dr. 
Fisher's  status.  Dr.  Ronald  Herberman,  the  director  of  the  Cancer 
Center  at  the  University  of  Pittsburgh  and  a  widely  respected  sci- 
entist, has  assumed  this  job  on  an  interim  basis.  An  interim  execu- 
tive officer  has  been  appointed  to  oversee  daily  operations.  An  over- 
sight committee  composed  of  experienced  oncologists,  breast  cancer 


51 

specialists,  and  a  consumer  advocate  has  been  appointed,  and  the 
membership  of  the  group  has  received  information  regarding  the 
fraud  and  operational  deficiencies  of  the  group. 

It  is  my  personal  belief  that  Dr.  Fisher  pioneered  and  established 
this  group  prior  to  even  the  founding  of  the  national  cancer  pro- 
gram in  its  current  iteration,  and  I  believe  that  is  a  fact  that  has 
partially  influenced  the  relationship  of  who  reports  to  whom.  The 
group  has  been  placed  on  probation,  and  it  has  until  the  end  of 
June  1994  to  initiate  programs  to  bring  its  auditing  and  reporting 
procedures  into  compliance.  Accrual  to  clinical  trials  has  been  tem- 
porarily suspended  until  these  deficiencies  are  correct  and  a  quality 
auditing  system  is  in  place. 

The  terms  of  awards  of  the  NSABP  grant  have  been  modified  to 
require  immediate  republication  of  any  trials  affected  by  fraud. 
Similar  grant  conditions  are  being  implemented  for  all  of  NCI's 
clinical  trials'  cooperative  groups.  Our  own  NCI  run  audits  of  var- 
ious hospitals  and  academic  centers  affiliated  with  this  group  con- 
tinues. We  are  attempted  to  recover  funds  expended  at  the  fraudu- 
lent data  site.  We  consider  the  entire  data  set  from  St.  Luc's  Hos- 
pital to  be  a  total  loss  to  the  American  taxpayers. 

We  have  learned  a  great  deal  about  the  process  and  pitfalls  of 
dealing  with  scientific  misconduct.  We  clearly  understand  the  prin- 
ciple that  we  cannot  allow  a  grantee's  formidable  reputation,  his- 
tory of  prior  accomplishments  or  service  in  science  to  stand  in  the 
way  of  prompt,  corrective  action  and  oversight.  Prior  achievements 
do  not  render  individuals  immune  to  what  we  must  get  from  them. 
We  cannot  and  will  not  ever  defer  or  appear  to  defer  to  the  time- 
table of  a  grantee  of  whatever  preeminence  in  reporting  fraud  and 
fabrication  to  the  public.  We  have  taken  steps  to  make  this  the  ex- 
plicit policy  of  the  National  Cancer  Institute. 

We  hope  that  the  measures  outlined  above  will  bolster  at  least 
in  part  the  confidence  of  the  Congress,  the  public,  and  the  medical 
community  in  our  clinical  trials  program  and  will  strengthen  the 
operation  of  our  productive  clinical  trials  groups,  most  of  whose 
members  honor  careful  and  honest  science  and  are  devastated  by 
episodes  of  fraud,  as  are  we  at  the  National  Cancer  Institute. 

I  thank  the  Chair  for  his  very  generous  permission  to  allow  me 
to  go  over  my  time  limit.  Thank  you  for  providing  me  this  oppor- 
tunity to  testify  and  present  the  facts  about  NCI's  role.  I  would  be 
pleased  to  answer  any  questions. 

Mr.  DiNGELL.  Thank  you,  Dr.  Broder,  for  a  very  helpful  state- 
ment. Dr.  Bivens? 

TESTIMONY  OF  LYLE  W.  BIVENS 

Mr.  BrvENS.  Mr.  Chairman,  I'm  pleased  to  have  the  opportunity 
to  review  for  the  subcommittee  the  response  of  the  Office  of  Re- 
search Integrity  to  the  allegations  of  scientific  misconduct  at  St. 
Luc  Hospital.  Although  the  Office  of  Research  Integrity  was  estab- 
lished in  June  1992  and  was  therefore  not  involved  in  the  case 
until  that  time,  I'll  attempt  to  provide  briefly  the  general  back- 
ground of  the  circumstances  leading  to  ORI's  specific  role  in  the 
case.  I'll  then  describe  the  nature  of  our  investigation  and  subse- 
quent activities.  I  beg  your  indulgence  for  some  duplication  here. 


52 

but  I  think  it's  important  for  the  record  for  me  to  cover  background 
material  leading  up  to  our  involvement. 

In  June  1990,  the  staff  of  the  National  Surgical  Adjuvant  Breast 
and  Bowel  Project,  a  large  collaborative  clinical  trial  supported  by 
the  National  Cancer  Institute,  discovered  discrepancies  in  two  re- 
ports of  breast  cancer  surgery  involving  an  individual  who  was  the 
study  subject.  This  woman  was  part  of  the  study  group  from  St. 
Luc  Hospital  in  Montreal,  one  of  the  many  hospitals  participating 
in  the  study. 

In  September  1990,  an  audit  by  NSABP  staff  identified  problems 
with  both  medical  records  and  documents  relating  to  the  informed 
consent.  Dr.  Poisson,  the  principal  investigator  for  the  St.  Luc  com- 
ponent of  the  study,  was  informed  about  these  problems  in  Decem- 
ber. 

Early  in  1991,  NSABP  reviewed  over  100  cases  and  found  five 
discrepancies  in  this  group.  These  discrepancies  had  the  effect  of 
making  five  patients  eligible  for  inclusion  in  the  study  who  would 
have  not  been  eligible  had  the  protocol  been  followed  properly. 

On  February  6,  1991,  Dr.  Bernard  Fisher,  the  principal  inves- 
tigator for  the  overall  project,  suspended  accrual  of  new  patients 
from  St.  Luc  and  asked  for  an  explanation  of  the  data  discrep- 
ancies. Dr.  Poisson  admitted  to  alteration  of  records  in  a  few  in- 
stances but  not  to  any  wrongdoing.  On  February  14,  NCI  received 
notification  from  Dr.  Fisher  that  irregularities  have  been  found  in 
the  data  from  St.  Luc. 

On  February  22,  some  8  months  after  the  initial  problems  were 
identified,  NCI  staff  met  with  Dr.  Fisher  at  Pittsburgh  to  discuss 
the  findings.  At  the  conclusion  of  the  meeting,  NIH's  office  of  sci- 
entific integrity  was  notified  by  NCI  of  apparent  fabrication  and 
falsification  of  the  data  from  St.  Luc.  NCI  also  notified  the  Office 
for  Protection  from  Research  Risks  and  the  FDA  because  of  in- 
formed consent  problems  and  the  fact  that  some  of  the  questioned 
data  had  been  filed  under  an  investigational  new  drug  application 
for  tamoxifen. 

OSI  immediately  decided  to  conduct  a  direct  investigation  due  to 
the  importance  of  the  NSABP  studies  in  changing  standards  for 
medical  practice. 

On  March  1,  1991,  OSI  opened  a  formal  investigation  and  di- 
rected that  all  records  for  the  patients  be  secured  and  maintained 
under  proper  custody.  OSI  developed  a  plan  to  audit  a  sample  of 
cases  entered  on  NSABP  studies  from  St.  Luc  hospital.  This  was 
a  complex  task.  Three  charts  were  maintained  for  each  case,  in  pa- 
tient records,  outpatient  records  and  research  records  and  the  med- 
ical records  were  in  French. 

An  OSI  team  along  with  staff  from  NCI,  NSABP  and  FDA,  made 
an  initial  visit  to  St.  Luc  Hospital  on  April  22  to  24,  1992,  to  re- 
view records  and  interview  St.  Luc  staff.  The  review  team  found 
that  5  to  10  percent  of  the  cases  in  the  sample  contained  what  ap- 
peared to  be  data  discrepancies.  OSI  decided  to  audit  records  of  all 
1,504  patients  from  St.  Luke  hospital  rather  than  a  sample  of 
cases,  as  was  the  original  intent.  Many  of  the  discrepancies  were 
altered  dates  of  procedures  or  tests  that  made  patients  eligible  for 
inclusion  in  the  research  protocol,  whereas  the  correct  information 
would  have  made  them  ineligible. 


53 

Subsequent  review  of  records  was  conducted  on  June  11  to  14 
and  25  to  28,  and  on  August  26  to  18.  Beginning  in  September,  OSI 
and  NCI  evaluated  all  the  information  and  documents  collected 
during  the  investigation  and  compiled  a  database  of  falsification 
and  fabrication  charges.  On  February  19  to  21,  1992,  OSI  revisited 
St.  Luc  hospital  to  confirm  details  on  questionable  cases. 

An  overriding  concern  from  the  beginning  of  this  investigation 
was  whether  the  scientific  basis  for  breast  cancer  treatment  strate- 
gies was  invalidated  bv  the  falsified  and  fabricated  records.  NCI 
and  OSI  requested  early  on  that  NSABP  determine  whether  clini- 
cal outcomes  were  changed.  It  was  requested  that  NSABP  revise 
the  research  records  with  the  questionable  data  excluded.  Oral  con- 
firmation was  provided  by  NSABP  in  July,  1991,  that  outcomes 
had  not  changed.  At  the  request  of  OSI,  NSABP  presented  the  re- 
analyzed data  to  OSI,  NCI,  and  NIH  staff  in  March  1992.  NCI  and 
OSI  statisticians  were  aware  that  this  was  a  preliminary  analysis, 
and  then  NSABP  was  asked  to  prepare  a  manuscript  to  publish  the 
re-analysis  by  the  time  the  misconduct  investigation  was  com- 
pleted. 

Because  the  preliminary  re-analysis  indicated  that  the  basic  find- 
ings of  the  study  remained  valid,  OSI  concluded  that  no  clinical 
alert  or  notice  was  necessary  and,  consistent  with  existing  policy, 
no  public  information  on  the  case  was  provided  while  the  investiga- 
tion was  underway. 

On  April  8,  1992,  the  OSI  again  visited  St.  Luc  Hospital,  this 
time  with  two  outside  experts  to  review  the  cases.  From  June 
through  November,  1992,  the  newly  established  Office  of  Research 
Integrity  examined  all  of  the  evidence,  prepared  a  detailed  written 
report  for  each  case,  solicited  responses  from  Dr.  Poisson  on  each 
case  and  prepared  an  overall  report  which  was  sent  pursuant  to 
our  standard  procedures  to  Dr.  Poisson  for  comment  in  November 
1992. 

Although  Dr.  Poisson  admitted  to  altering  records  early  in  our 
investigation,  his  admissions  were  very  limited  and  provided  in  a 
piecemeal  fashion,  only  after  further  discrepancies  were  noted  as 
our  audits  proceed.  It  was  essential  for  investigation  to  uncover  the 
full  extent  of  the  misconduct,  especially  because  of  the  potential 
clinical  significance  of  the  data  in  question.  Therefore,  we  did  not 
stop  our  process  as  soon  as  Dr.  Poisson  made  a  very  limited  admis- 
sion. 

On  January  5,  1993,  the  NCI  sent  a  letter  to  Dr.  Fisher  urging 
finalization  of  the  manuscript  on  reanalysis  of  the  published  stud- 
ies. On  February  19,  1993,  ORI  notified  Dr.  Poisson  of  our  findings 
and  proposed  actions,  including  his  debarment  from  receiving  Fed- 
eral grant  or  contract  funds  for  years.  Copies  of  our  notice  and  final 
report  were  also  sent  to  NIH,  St.  Luc  Hospital,  and  the  University 
of  Pittsburgh.  At  the  same  time,  I  wrote  a  memorandum  to  the  di- 
rector of  NCI  summarizing  OKI's  recommendations  for  publication 
of  the  reanalyzed  studies. 

Under  a  newly  establish  hearing  opportunity  for  scientists 
charged  with  misconduct.  Mr.  Poisson  had  30  days  after  initial  no- 
tification to  request  a  hearing.  He  did  not  do  so,  and  ORI  made  its 
findings  final  effective  March  29  and  notified  Dr.  Poisson  of  this  on 
April  16. 


54 

At  about  the  time  that  this  case  was  being  concluded,  ORI  had 
decided  that  it  was  in  the  public  interest  to  provide  wide  notice  of 
our  findings  of  scientific  misconduct.  This  was  a  major  departure 
from  the  practice  of  our  predecessor  organizations  in  which  infor- 
mation on  cases  of  confirmed  scientific  misconduct  was  released 
only  in  response  to  requests  under  the  Freedom  of  Information  Act. 
A  Federal  Register  notice  was  prepared,  summarizing  all  fourteen 
of  the  cases  of  scientific  misconduct  that  had  been  closed  since  ORI 
was  established  in  June  1992,  and  this  notice  was  published  on 
June  21,  1993. 

We  also  published  the  identical  information  in  the  NIH  guide  to 
grants  and  contracts,  a  weekly  publication  sent  to  more  than 
30,000  institutions,  hospitals,  ana  organizations  concerned  with 
NIH  research.  We  described  the  St.  Luc  case  in  the  April  issue  of 
the  ORI  newsletter,  which  is  sent  to  all  institutions  receiving  pub- 
lic health  service  research  funds,  as  well  as  to  a  large  number  of 
professional  and  scientific  organizations. 

In  addition,  we  issued  a  brief  press  release  announcing  findings 
in  the  14  completed  investigations,  including  the  St.  Luc  investiga- 
tion. In  addition  to  these  releases,  we  provided  the  full  report  of 
our  investigation  of  St.  Luc's  hospital  in  response  to  six  requests 
under  the  Freedom  of  Information  Act.  Two  of  these  requests  were 
from  the  media  and  four  were  from  institutions  or  individuals. 

If,  during  the  course  of  the  investigation,  ORI  had  identified  any 
immediate  threat  to  the  scientific  basis  for  breast  cancer  treatment 
strategies,  we  would  have  taken  immediate  steps  to  alert  the  public 
and  those  making  treatment  decisions  based  on  those  studies. 
There  was  no  such  indication,  so  we  adhered  to  our  standard  proce- 
dure, waiting  until  the  investigation  was  complete  before  releasing 
information. 

I  believe  that  ORI  properly  discharged  its  responsibilities  in  this 
case,  conducting  a  thorough  and  objective  investigation  and  dis- 
seminating the  findings  widely.  However,  it  is  also  clear  from  this 
case  that  we  can  improve  our  effectiveness  when  we  find  mis- 
conduct in  science.  Consequently,  we  have  initiated  a  number  of 
changes.  First,  we've  instituted  a  policy  to  routinely  and  directly 
notify  journal  editors  of  our  findings  whenever  it  appears  that  cor- 
rections or  retractions  of  the  scientific  literature  are  warranted. 

Second,  we're  working  more  closely  with  the  PHS  funding  agen- 
cies in  following  up  our  recommendations  when  misconduct  is 
found  or  even  in  cases  where  there  is  no  misconduct  but  some  re- 
medial action  seems  required.  We  established  a  process  whereby 
we  request  a  report  within  45  days  of  our  notifying  a  PS  funding 
agency,  and  that  certain  actions  will  be  taken.  This  will  assure  that 
ORI  recommendations  are  flagged  for  the  PHS,  and  acted  upon  in 
a  more  effective  and  coordinated  fashion  by  the  Department. 

Third,  and  perhaps  most  important,  based  upon  the  testimony  I 
heard  this  morning,  I  believe  that  ORI  should  provide  a  higher  vis- 
ibility press  release  at  the  conclusion  of  any  investigation  finding 
misconduct  in  a  clinical  trial  whether  the  findings  of  the  trial  are 
invalidated  or  not.  If  we  had  done  this  in  the  present  case,  it  might 
have  allayed  unnecessary  concerns  about  the  validity  of  the  find- 
ings of  the  study.  This  was  our  first  finding  of  scientific  misconduct 
in  a  clinical  trial,  and  our  overriding  concern  was  whether  or  not 


55 

there  was  any  immediate  need  to  provide  the  medical  community 
with  some  sort  of  clinical  alert  that  the  scientific  basis  for  a  treat- 
ment strategy  might  be  called  into  question.  However,  it  is  clear 
that  we  also  need  to  attend  to  the  concerns  and  perceptions  of 
those  persons  most  directly  affected  by  the  clinical  research  in 
question. 

I'll  be  pleased  to  respond  to  any  questions. 

Mr.  DiNGELL.  Thank  you  very  much,  Doctor,  for  your  very  wel- 
come statement.  Dr.  Broder,  you  were  speaking  on  behalf  of  the 
NCI.  Dr.  Varmus,  you're  here  speaking  on  behalf  of  the  National 
Institutes. 

In  order  that  we  have  a  record  which  is  clear,  do  you  at  the  Na- 
tional Institutes  of  Health  endorse  the  statement  that  was  made  by 
Dr.  Broder? 

Mr.  Varmus.  Yes,  I  do. 

Mr.  DiNGELL.  You  do.  So  that  essentially  becomes  the  statement 
of  both  NCI  and  the  National  Institutes  of  Health  and  the  policies 
therein,  then,  as  enunciated  by  Dr.  Broder,  the  policies  of  NIH.  Is 
that  right? 

Mr.  Varmus.  In  principle,  of  course,  the  specifics 

Mr.  DiNGELL.  I  was  comfortable  till  you  said  it  "in  principal",  at 
which  point  my  discomfort  level  rose. 

Mr.  Varmus.  I  would  just  make  clear  that  the  specific  remedi- 
ation procedures  that  Dr.  Broder  was  specifying  apply  to  his  insti- 
tute. Other  institutes  have  very  similar  measures.  They  may  not  be 
identical.  I'd  want  to  check  them. 

Mr.  DiNGELL.  I  think  you  are  compelling  us  to  inquire,  then,  as 
to  the  similarities  and  to  get  some  appreciation.  Would  you  submit 
to  us  the  remediation  procedures  at  the  different  institutes  so  that 
we  can  see  whether,  in  fact,  they  meet  your  test  or  Dr.  Broder's 
test? 

Mr.  Varmus.  We  can  do  so. 

Mr.  DiNGELL.  It  may  be  that  there  are  some  who  are,  let's  say, 
not  being  as  vigorous  as  you  and  I  would  like  them  to  be  and  I 
think  we'd  like  to  have  a  little  look  at  that. 

Mr.  Varmus.  May  I  say,  Mr.  Chairman,  that  Wendy  Baldwin,  the 
Deputy  Director  for  Extramural  Activities,  who  is  sitting  behind 
me,  was  asked  by  me  a  few  weeks  ago  to  look  at  the  other  insti- 
tutes' activities.  I've  been  very  pleased  with  what  she's  found  and 
I  think  you  will  agree  that  they  meet  the  high  standards  you  would 
like  to  see  in  place. 

Mr.  DiNGELL.  Thank  you.  Doctor.  Dr.  Broder,  the  representative 
of  the  Breast  Cancer  Coalition  complained,  and  I  think  properly  so, 
about  the  lack  of  information  regarding  the  B-14  treatment  trial. 
Just  last  Friday,  FDA  and  ICI/Zeneca,  the  manufacturer  of 
tamoxifen,  issued  a  new  warning  and  label  based,  in  part,  on  the 
findings  of  at  least  four  cancer  deaths  associated  with  the  adminis- 
tration of  tamoxifen  in  that  trial. 

The  subcommittee  has  recently  obtained  from  Dr.  Fisher  a  chro- 
nology of  events  related  to  the  deaths  of  these  women  and  submit- 
ted it  to  NCI  for  review.  What  conclusions  did  NCI  draw  from  your 
review  and  the  analysis  of  the  timeliness  of  the  disclosures  of  the 
deaths  of  those  patients? 


56 

Mr.  Broder.  Sir,  members  of  your  committee  were  kind  enough 
to  give  me  some  information  which,  in  part,  we  did  not  have.  I  was 
able  to  review  them  last  night. 

It  is  my  professional  judgment  that  we  should  have  received  in- 
formation on  certain  facts  and,  particularly,  if  it  would  be  possible, 
to  have  information  on  endometrial  cancer  early  in  1992,  possibly 
earlier,  and  that  information  was  not  provided  to  us  until  substan- 
tially later  than  that. 

This  speaks  to  the  issue  of  us  wanting  to  hold  the  IND  for  such 
studies,  which  we  did  not  have.  But  there  was  no  information  pro- 
vided and  I  believe  that  early  in  1992,  certain  information  about 
an  endometrigd  cancer  death  could  have  been  provided  to  us. 

Mr.  DiNGELL.  So  it  would  be  fair  to  say  that  one  of  the  deaths 
should  have  been  understood  and  reported  in  early  1992.  Is  that 
fair? 

Mr.  Broder.  That's  correct.  I'm  trying  to  be  fair  and  physicians 
may  have  their  own  interpretation.  This  particular  patient  was  ini- 
tially signed  out  as  a  pulmonary  embolism,  or  at  least  that's  the 
facts  as  I  know  them.  Since  the  diagnosis  had  pulmonary  embolism 
in  it  as  the  cause  of  death,  I  believe  there  was  some  legitimate 
basis  for  not  making  a  decision.  But  I  personally  believe  1992 
would  be  fair. 

Mr.  DiNGELL.  Without  objection,  we'll  put  the  chronology  of  that 
in  the  record. 

[The  information  follows:] 


57 


i->  ;:  z 


ft  s 


0> 


?  2  O 

£  —  .  uj 

=  Z  O  = 

*^  o  >-  es 

S  UJ  ^  >- 


01 

fM 


(SI 


fM 


0.    0\ 


(M 

» 

(M 

I 


(M 


K-  e  Kj 

Wfl  (1  Z 

s  _  >^ 

-  l^  M 


ss 

m  —  IV 

a>   CA  B> 

ea  o  lo  (N  — 
sa  0>  91  »  ON 

? 

a  cji  m  — 

G9   GS  »  CI 

ot  u> 
1     1 

—  a 

1  —  e  a 
1  a  —  to 

N  «  ~  e  e 
1  (M  —  o  in  — 

.  a   1 
*  »-   1 

1  pg  B  '  a 
1  pg  Kl  a  — 

1  m  a 

s: 

e  e  B 

—  O  (M  —  — 

a  —  s  e  « 

a 

a  a  a  a 

—  pg 
a  a 

s§ 


2=    - 

K  i  u  s 

>-  (J  O  taJ 

M  w  a  e 
=  -I  Z  a 


pg  —  K>  PM  a  pg  Ki 
at  ON  0«  ot  0>  e>  *> 


0<  PM  —  a 


r-  <r  m  o> 


I  I  I  I 


►n  a  Bi  -• 
Q^  a*  o^  *^  ' 


tz 


«i  lo  m  pg  e«  vD  vo 


pipgoS;  —  pgfoin 

_        1     I     I   Wl    I     1     I     I 

R-.SSSpgSrvSa-S-BgNBBB 
-■-— to  —  efiS  —  (M 


et  10  tn 


^  a  —  —  k  Z  I 


N  r- 


1/1 


>£>  5  =  B  - 


pg  a  pg  — 
^  a>  »  o> 


pg  trt 

.    .    -     .  "»  ^.  • 
pg  p«(  pg  <o  (o  It 


pg  — 
01  01 


—  a  (M  —  pg  pg  o 
B>  et  ct  0t  0<  0>  01 


mwwmoiieot  —  0ipJ>'ipgsSP''|g 


Z       w 


s 

CM  —  a  —  miaoipg  —  apgMioin«« 
ea0i9oichaa0i0>0i0>9at0\aB 

a 
pg 

iaetpgpgtar'«ae><£csa  —  BtiaaiPi 
m  —  e  —  pg-'saae  —  loaaaip)-- 

01 

TJ.4---p:-ip!i-«^2!C!2a2a 

■t  a>  01  a  pg  P>J  d 
a  a  0  01  9  0t  ot 


m  01  ID  v« 

—  M  —  a 


o       a 
Z        Z 


58 

Mr.  DiNGELL.  Now,  is  it  fair  to  say  that  the  NCI  and  the  manu- 
facturers should  be  notified  in  1993  about  a  second  death? 

Mr.  Broder.  That's  fair. 

Mr.  DiNGELL.  The  notification  of  the  third  death  should  have  oc- 
curred by  at  least  January  1993,  isn't  that  so? 

Mr.  Broder.  I  believe  that  that's  fair. 

Mr.  DiNGELL.  So  you  have  three  and  then  the  fourth  death,  there 
should  have  been  a  notification  by  at  least  August  of  1993,  isn't 
that  right? 

Mr.  Broder.  Sir,  I  believe  that's  correct,  but  if  that  specific 

Mr.  DiNGELL.  I'm  not  going  to  hold  you  to  something.  You  con- 
sider yourself  free  to  respond  to  that  question  later,  as  the  need 
might  occur. 

Mr.  Broder.  Yes.  Recognizing  that  there  might  be  a  minor  devi- 
ation from  that  specific  date.  But  I  do  take  your  point  and  I  believe 
it's  substantively  correct. 

Mr.  DiNGELL.  When  were  you  notified.  Doctor? 

Mr.  Broder.  Sir,  we  received  our  notification  through  an  NSABP 
meeting  that  was  held  in  October — toward  the  end  of  October  of 
1993. 

Mr.  DiNGELL.  Substantially  later  than  the  time  that  you  should 
have  been  notified. 

Mr.  Broder.  You  are  correct. 

Mr.  DiNGELL.  Doctor,  is  it  your  testimony  that  the  American  pub- 
lic should  be  informed  about  the  deaths  associated  with  tamoxifen, 
as  well  as  increased  cancers  associated  with  tamoxifen  in  1992,  not 
1994? 

Mr.  Broder.  I  believe  that  an  appropriate  notification  should 
have  started  early  in  1992. 

Mr.  DiNGELL.  Here  we  have  a  bunch  of  women  who  have  partici- 
pated in  a  test.  They  were  advised  of  certain  matters  in  connection 
with  this  to  achieve  their  informed  consent.  The  testimony  so  far 
indicates  that  they  may  not  have  been  properly  and  adequately  ad- 
vised to  give  their  full  and  adequate  consent  based  on  a  fair  expo- 
sition of  the  facts  and  the  risks  and  the  data  available  to  the  exam- 
iners. 

Is  that  a  fair  statement? 

Mr.  Broder.  I  believe  it  is  fair.  But  if  you  will  permit,  the  situa- 
tion has  a  complexity  in  that  the  very  first  informed  consent  did 
disclose  to  patients  the  possibility  of  lethal  outcomes.  They  were  re- 
lated to  embolic,  thrombophlebitic  and  cardiovascular.  So  the  pa- 
tients were  on  notice  that  death  was  a  possibility. 

The  patients  were  also  on  notice  that  endometrial  cancer  was  a 
possibility.  But  you  are  quite  right  and  I  believe  your  point  is  well 
taken  that  the  issue  of  endometrial  cancer,  which  should  have  been 
brought  up  to  current  state,  was  not  provided. 

Mr.  DiNGELL.  The  risk  with  regard  to  uterine  cancer  was  either 
not  stated  or  was  significantly  understated. 

Mr.  Broder.  The  risk  of  death  from  uterine  cancer  most  as- 
suredly was  not  properly  and  adequately  provided. 

Mr.  DiNGELL.  As  a  matter  of  fact,  was  there  any  information  at 
all  with  regard  to  possible  fatalities  resulting  from  this? 

Mr.  Broder.  Death  to  certain 

Mr.  DiNGELL.  From  uterine  cancer. 


59 

Mr.  Broder.  From  uterine  cancer,  no.  But  death  due  to  other 
causes  was — the  patients  were  put  on  notice  that  there  was  a  pos- 
sibility of  a  lethal  outcome  from  exposure  to  tamoxifen. 

Mr.  DiNGELL.  Is  there  any  requirement  now  in  the  protocols  or 
the  rules  and  regulations  of  either  NCI  or  NIH  that  would  require 
women  to  be  properly  notified  in  connection  with  the  risks? 

Mr.  Broder.  What  we  are  doing  now  is  that  we  are  reexamining 
and  will,  as  a  condition  of  a  grant,  require  the  same  kind  of  notifi- 
cation that  the  grantee  would  owe  to  the  IND  holder.  We  want  to 
be  in  the  information  loop  immediately,  not  as  an  afterthought.  We 
are  prepared  to  not  fund  proposals  where  that  is  not  possible. 

In  a  community-based  study,  which  is  far  flung  and,  by  defini- 
tion, has  a  number  of  sites  at  multiple  areas  and  also  has  central 
pathology  services  and  other  things  that  need  to  be  done,  one  has 
to  accept  a  certain  amount  of  delay.  Also,  there  is  a  need  to  make 
sure  that  if  an  alarm  is  sounded,  that  it  is  based  on  very  valid  in- 
formation so  that  the  meaning  of  the  alarm  would  be  preserved. 

With  all  of  that,  I  think  that  our  processes  need  to  be  improved 
and  we  are  taking  steps  to  make  sure  that  the  grantee  understands 
that.  We  will  also  strongly  discourage  either  the  private  companies 
or  the  individual  grantees  from  holding  the  IND,  which,  in  effect, 
was  the  case  here  for  the  tamoxifen  studies. 

Mr.  DiNGELL.  Doesn't  it — I'm  sorry.  Dr.  Varmus,  go  ahead. 

Mr.  Varmus.  It  is,  of  course,  NIH  policy  that  all  of  our  consent 
forms  reveal  all  of  the  relevant  information  that  would  constitute 
risk  to  patients  enrolled  in  these  studies.  We  ask  our  Office  of  Pro- 
tection from  Research  Risks  and  the  Institutional  Review  Boards, 
which  include  members  of  the  public,  often  consumers  who  are  in- 
volved in  these  studies,  to  be  sure  that  the  consent  forms  do  ade- 
quately describe  all  of  the  known  risks. 

Mr,  DiNGELL.  Have  all  of  the  women  who  were  put  at  risk  by  the 
failure  to  adequately  disclose  the  risk  levels  with  regard  to  uterine 
cancer  or  other  perils  been  informed  of  the  new  level  of  risk  or  the 
level  of  risk  as  we  now  know  it? 

Mr.  Broder.  I'd  like  to  ask  Dr.  Friedman  to  comment  on  where 
we  are  with  that  process. 

Mr.  DiNGELL.  They  either  had  been  advised  or  they  had  not  been 
advised.  We  can  get,  I  think,  a  fairly  simple  yes  or  no  answer. 

Mr.  Broder.  In  that  case,  the  answer  is  no. 

Mr.  DiNGELL.  The  answer  is  no. 

Mr.  Broder.  The  process  in  large,  far-flung,  community-based 
studies  requires  several  steps.  We  could  theoretically  provide  notice 
of  some  type.  A  local  institutional  review  board  not  responding  to 
the  government  must  approve  and  endorse  any  changes  in  in- 
formed consents. 

We  do  try  to  make  the  information  as  publicly  available  as  we 
can,  but  I  cannot  assure  you  that  every  single  woman  has  signed 
a  new  informed  consent. 

Mr.  DiNGELL.  I'm  trying  to  understand.  We  have  many  questions 
here,  one  of  which  is  the  simple  moral  question.  Shouldn't  these 
women  be  informed  of  the  fact  that  they  have  been  put  at  addi- 
tional risk  which  was  not  disclosed  to  them  at  the  time  they  agreed 
to  participate  in  the  study? 


60 

Mr.  Broder.  Yes.  And  that  process  is  going  on  now  and  will  be 
completed.  If  your  question  is  will  every  single  woman  be  notified, 
the  answer  is  yes. 

Mr.  DiNGELL.  When  will  that  occur?  Because  they  are  now  all  at 
additional  risk  with  regard  to  uterine  cancer,  some  also  with  re- 
gard to  blood  pressure  and  possibly  other  matters.  When  will  they 
receive  notice? 

Mr.  Varmus.  Mr.  Chairman,  all  of  the  309  sites  of  the  tamoxifen 
prevention  study  have  been  informed  of  the  recommendations  to 
change  the  consent  forms  to  be  in  accord  with  the  newly  available 
evidence.  Now,  of  course,  it  is  the  responsibility  of  those  who  are 
in  charge  of  the  study  at  each  of  those  sites  to  respond  and  to  in- 
form each  of  the  patients. 

The  NCI  itself,  of  course,  can't  inform  the  patients  directly.  We're 
informing  them  through  the  several  hundred  sites  that  are  partici- 
pating in  this  multi-institutional  study. 

Mr.  DiNGELL.  Have  you  told  me  that  all  of  the  women  have  been 
informed  or  just  that  the  sites  have  been  informed? 

Mr.  Varmus.  All  of  the  sites  have  been  informed  and  we  hope, 
we  trust,  and  we  will  enforce  the 

Mr.  DiNGELL.  One  of  the  great  charities  or  one  of  the  three  great 
virtues.  But  this  committee  has  always,  in  dealing  with  matters  of 
this  kind,  sought  greater  res^^onse  from  the  government  than  sim- 
ply trust  in  the  great  virtues. 

I'm  curious.  How  are  we  to  say  that  the  sites  have  informed  the 
women?  We  cannot  say  so,  can  we? 

Mr.  Broder.  Mr.  Dingell,  you  are  quite  right  to  raise  this  issue. 
The  trial  is  currently  suspended.  We  have  taken  our  process  of  how 
one  informs  women  of  new  and  evolving  side  effects  to  the  Office 
of  Protection  from  Research  Risks,  which  advises  us  in  that  proc- 
ess. 

Perhaps  you  might  also  wish  to  take  into  account  the  fact  that 
in  any  study  there  will  be  an  ongoing  process  of  new  risks,  some 
of  them  acute,  some  of  them  longstanding,  and  some  of  them  chron- 
ic. There's  always  going  to  be  an  updating  process.  So  this  is  not 
the  only  time.  We're  going  to  have  to  continuously  modify  our  in- 
formed consent. 

The  Office  of  Protection  from  Research  Risks  advised  us  that 
upon  their  evaluation,  this  process  did  not  require  an  immediate 
call-back  notification,  but  could  be  done  in  the  normal  cycle  in 
which  women  would  come  back  to  clinic.  We,  however,  have  chosen 
not  to  take  that  option  and  we  will  be  calling  women  back. 

In  addition,  we  will  have  a  process  to  ensure  that  sites  have  noti- 
fied all  women  before  that  site  can  re-accrue  women  in  the  process 
when  the  current  suspension  is  over. 

Mr.  DiNGELL.  I  hear  a  goodly  number  of  things,  but  we  have  es- 
tablished clearly  that  we  cannot  say  that  the  women  have  been  no- 
tified. 

Mr.  Broder.  I  cannot  tell  you  that  every  single  woman  has  been 
notified. 

Mr.  DiNGELL.  We've  also  come  to  the  conclusion,  and  I  think  you 
concur  in  this.  Dr.  Varmus,  that  there  is  a  moral  requirement  that 
the  women  who  participated  in  this  study  should  be  given  correct 
information  about  new  risks  which  have  come  to  light  since  the 


61 

time  that  the  study  was  initiated  and  since  they  were  advised  of 
the  level  of  risk.  Is  that  not  so? 

Mr.  Varmus.  Yes,  I  agree  with  that. 

Mr.  DiNGELL.  And  we  can  establish  that  we  do  not  know,  but  we 
hope  that  the  women  have  been  informed  by  the  sites.  Now,  we  can 
observe  fairly  that  the  women  involved  in  the  test  are  probably  still 
taking  the  drug,  can  we  not? 

Mr.  Vaemus.  Mr.  Chairman,  we  will  be  in  touch  with  every  one 
of  those  sites  to  ensure  that  every  woman  who  is  enrolled  at  those 
sites  has  received  the  information. 

Mr.  DiNGELL.  That  has  not  yet  occurred. 

Mr.  Varmus.  That's  correct. 

Mr.  DiNGELL.  We  also  have  a  modest  little  problem  in  the  fact 
that  the  women  should  be  informed  so  that  they  can  know  what 
the  new  level  of  risk  might  be.  We  also  had  the  additional  problem 
that  there  is  no  requirement  in  the  rules  or  regulations  of  NIH  that 
the  women  do  receive  notification  of  changes  in  the  level  of  risk  to 
them  from  this  particular  test  program  of  which  they  have  become 
a  part.  Is  that  not  so? 

In  other  words,  there  is  no  requirement  in  the  program  that  the 
women  be  warned  of  changes  in  risk  as  they  occur  to  them  or  in 
incorrect  representations  to  them  of  the  level  of  risks  which  were 
made  early  on  to  induce  their  participating  the  program. 

Dr.  Chabner,  do  you  want  to  comment  on  that? 

Mr.  Chabner.  Yes.  There  is  an  absolute  responsibility  to  notify 
participants. 

Mr.  DiNGELL.  You  agree  there's  a  responsibility,  but  what  is 
there  in  the  regulations? 

Mr.  Chabner.  Yes.  The  IND  holder  must  notify  participants  in 
a  trial. 

Mr.  DiNGELL.  You  can,  but  this  has  not  been  done  and  it  is  not 
in  the  regulations  at  NIH  to  require  the  women  to  be  informed,  is 
it?  Yes  or  no? 

Mr.  Chabner.  I'm  not  sure. 

Mr.  DiNGELL.  Well,  that's  a  good  answer.  It  tells  me  that  there 
is  no  requirement  at  NIH. 

Mr.  Chabner.  I  know  it's  a  requirement  for  the  IND  holder. 

Mr.  DiNGELL.  Maybe  Dr.  Friedman  or  Dr.  Broder  or  Dr.  Varmus 
can  tell. 

Mr.  Broder.  Mr.  Dingell,  I'll  shortcircuit  the  issue.  I  will  just 
speak  for  the  NCI.  There  is  a  requirement. 

Mr.  DiNGELL.  There  is  a  requirement? 

Mr.  Broder.  I'm  saying  there  is  a  requirement. 

Mr.  Dingell.  Has  that  requirement,  then,  been  honored  here? 

Mr.  Broder.  It  has  not  been  honored  from  the  point  of  as  we 
speak  today. 

Mr.  DiNGELL.  But  as  we  speak  today,  women  are  taking 
tamoxifen.  And  as  we  speak  today,  women  are  not  being  informed 
of  the  level  of  risk  that  they  confront.  As  we  speak  today,  women 
are  not  able  to  go  to  their  own  doctor  and  say  ,"Doctor,  should  I 
continue  in  this  research  program  with  a  potentially  increased  level 
of  risk."  Nor  are  they  being  informed  that  they  can  have  their  own 
doctors  inquire  and  to  monitor  with  greater  care  into  their  level  of 
safety. 


62 

Mr.  Broder.  If  I  could  say,  the  methods  that  we — we  cannot, 
under  current  operating  rules,  command  an  institution  to  adopt  our 
informed  consents.  But  we  will  reexplore  that  issue  even.  What  we 
are  trying  to  do  is — the  process  involves  sending  out  changes.  One 
of  the  points  I  would  like  to  stress  is  that  there  will  be  many 
changes.  There  are  new  things  that  one  learns  in  any  study. 

So  we  have  a  process.  This  will  not  be  the  last  time  we  will 
change  this  informed  consent  or  others.  What  we  are  trying  to  do 
in  the  interim  is  notify  women  in  a  number  of  ways,  notify  women 
through  the  cancer  information  service,  which  women  can  call,  no- 
tify them  through  our  electronic  data  boards.  A  letter  from  Zeneca 
is  in  our  PDQ  and  cancer  facts  system. 

In  other  words,  we  are  doing  what  we  can  to  get  the  word  out. 
We  will  have  rules  in  place  so  that  accrual  cannot  start  and  insti- 
tutions will  need  to  document  for  us  that  all  women  have  been  in- 
formed. But  you  are  right  that  the  process  has  a  certain  delay  ele- 
ment in  it. 

Mr.  DiNGELL.  But  here  you  have  the  good  Dr.  Fisher,  the  Univer- 
sity of  Pittsburgh,  all  the  grant  recipients,  all  the  folks  who  are 
participating  in  the  study,  and  you  have  imposed  no  requirements 
on  them,  as  the  record  stands  at  this  particular  time,  requiring 
them  to  report  to  the  participants  in  the  study  of  new  information 
relative  to  risk,  nor  of  increased  risk  which  has  come  to  your  atten- 
tion. 

You're  doing  all  this  wonderful  work  and  I  appreciate  that,  but 
you're  not  imposing  any  requirement  on  the  dear  University  of 
Pittsburgh  or  the  good  Dr.  Fisher  to  get  this  information  to  people 
who  may  potentially  be  put  at  risk  by  the  changes  in  the  cir- 
cumstances, by  the  new  information,  and  by  the  failure  to  ade- 
quately warn  them  back  in  1992. 

Is  that  a  fair  statement  or  not? 

Mr.  Chabner.  Congressman,  the  University  of  Pittsburgh,  Dr. 
Fisher,  holds  the  IND  in  this  trial.  They  have  a  legal  obligation  to 
notify  participants  in  their  trial.  That  is  an  obligation. 

Mr.  DiNGELL.  Have  they  done  that? 

Mr.  Chabner.  They've  been  instructed  to  do  it.  Whether  they've 
done  it  or  not 

Mr.  DiNGELL.  They  seem  to  be  somewhat  deficient  in  following 
up  on  instructions,  according  to  what  we've  gotten  today. 

Mr.  Broder.  We  take  your  point. 

Mr.  DiNGELL.  Remember,  the  IND,  that's  the  investigation  on  the 
new  drug,  is  that  right?  That  is  not  an  NIH  requirement. 

Mr.  Broder.  That's  correct. 

Mr.  DiNGELL.  That  is  a  Food  and  Drug  requirement,  right? 

Mr.  Broder.  Yes.  But  as  a  requirement  to  get  the  grant,  they 
must  have  the  IND. 

Mr.  DiNGELL.  Pardon? 

Mr.  Broder.  It  is  our  requirement,  in  order  to  do  the  study,  they 
must  have  an  valid  IND.  So  if  their  IND  is  revoked  or  improperly 
being  performed,  then  the  study  must  stop. 

Mr.  DiNGELL.  It  probably  is  too  much  to  say  they've  been  snap- 
ping their  finger  under  your  nose,  but  certainly  their  behavior  has 
been  less  than  the  requirements  that  you  would  impose  on  them 


63 

in  terms  of  good  moral  behavior  or  in  terms  of  seeing  to  it  that  the 
experiment  is  conducted  in  a  sound  scientific  fashion. 

Mr.  Broder.  They  don't  respond  to  constructive  criticism. 

Mr.  DiNGELL.  Well,  we're  going  to  help.  We  think  that  now  we 
maybe  ought  to  have  the  University  of  Pittsburgh  before  us  to  dis- 
cuss these  things.  Maybe  we  might  have  you  and  Dr.  Varmus  back, 
and  maybe  Dr.  Chabner  and  Dr.  Friedman  and  maybe  even  Dr. 
Bivens,  because  we  sense  that  matters  are  not  being  handled  in  a 
way  which  makes  this  information  fully  available  to  the  women 
who  have  been  involved  in  the  test. 

The  women  are  already  in  the  treatment  trial.  Many  have  taken 
the  drug  for  as  long  as  10  years. 

Mr.  Broder.  For  therapy  of  breast  cancer,  that's  correct.  They 
take  it  for  multiple  years. 

Mr.  DiNGELL.  And  some  are  taking  it  as  a  preventative.  Now, 
there  appears  to  be  strong  evidence  that,  in  point  of  fact,  it's  not 
a  good  preventative  and  there  also  appears  to  be  some  significant 
evidence  that  it  imposes  additional  risk  stemming  from  potential 
other  perils;  i.e.,  uterine  cancer  and  blood  pressure  phenomena. 

Mr.  Broder.  May  I  respond  to  that? 

Mr.  DiNGELL.  But  neither  you  nor  Dr.  Varmus  are  able  to  tell  us 
that  this  information  has  been  made  available  to  the  women  who 
are  involved  in  the  study.  We  are  trusting  the  Food  and  Drug  Ad- 
ministration, which,  not  infrequently,  we  have  before  this  commit- 
tee to  discuss  some  of  their  shortcomings. 

Mr.  Broder.  Mr.  Dingell,  I  take  your  point.  Perhaps,  with  your 
permission,  I'd  like  to  ask — well,  Dr.  Ford  has  not  been  sworn  in. 
I  will  certainly  provide  to  you  for  the  record  the  steps  that  we  have 
taken. 

But  if  you  will  permit  me  a  very  brief  interval.  You  made  a  state- 
ment which  I  would  argue  is  still  open  to  some  discussion.  We  un- 
derstand, respect  and  fear  breast  cancer.  It  is  an  invasive  disease 
and  a  woman  who  develops  breast  cancer  has,  in  spite  of  all  the 
best  things  that  we  have  to  offer  and  we  have  had  improvements, 
but  on  average,  a  woman  who  develops  breast  cancer  has  approxi- 
mately a  50  percent  chance  of  dying  of  her  disease. 

I  come  to  you  to  this  table  with  an  appreciation  of  the  formidable 
quality  that  breast  cancer  has.  We  do  not  have  any  immediate  pre- 
ventions to  offer  women  who  are  at  high  risk.  Some  women,  under 
50  and  over  50,  have  risk  factors  which  we  can  identify  that  impose 
an  enormous  burden  of  the  possibility  of  breast  cancer  for  them 
and  they  don't  have  any  options. 

What  we  are  saying  by  the  tamoxifen  study  is  that  certain 
women  who  have  high  risk  of  breast  cancer  can  possibly — we  will 
possibly  learn  whether  tamoxifen  could  be  a  preventative  for  those 
women.  We  have  certain  things,  like  hormonal  replacement  ther- 
apy, which  is  available  in  this  country  in  any  drug  store  by  a  pre- 
scription, which  causes  certain  benefits  to  women  who  are  post- 
menopausal, but  which  is  associated  with  a  comparable 
endometrial  cancer  risk,  and  it's  never  been  the  subject  of  a  clinical 
trial. 

All  we  are  saying  is  that  we  understand  the  problems,  but 
tamoxifen  has  been  one  of  the  few  things  in  the  scientific  literature 


64 

which  has  a  proven  and  multiply  replicated  reduction  of 
contralateral  breast  cancer  in  women  who  already  have  had 

Mr.  DiNGELL.  Doctor,  we  do  not  talk  about  it  as  a  useful  treat- 
ment device  for  breast  cancer. 

Mr.  Broder.  Even  for  prevention. 

Mr.  DiNGELL.  I  do  not  quarrel  about  that. 

Mr.  Broder.  What  I'm  talking  about  is  it  is — what  we  have 
learned  is  that  women  who  have  breast  cancer  have  a  separate  and 
independent  risk  not  only  of  recurrence,  which  is  one  problem  and 
is  the  most  often  thing  we're  talking  about,  but  they  have  an  inde- 
pendent risk  of  developing  a  new  breast  cancer  in  the  opposite 
breast. 

Tamoxifen  has  been  shown  to  reduce  that  in  several  studies  by 
a  substantial  amount.  Therefore,  it  also  possibly  may  have  certain 
effects  for  myocardial  infarctions  and  so  on.  Women  who  already 
have  breast  cancer  who  have  received  tamoxifen  have  fewer  heart 
attack  rates  than  the  control  group. 

We  are  not  saying  that  tamoxifen  should  be  used.  We  ask  for  it 
not  to  be  used  for  prevention.  What  we  are  saying  is  for  women 
who  are  at  risk,  we  ask  for  the  opportunity  to  do  a  clinical  trial 
so  that  we  can  inform  you  and  the  public  as  to  whether  this  is  an 
option.  That's  all  we  are  saying. 

Mr.  DiNGELL.  Let  us  lay  this  matter  to  rest.  I  am  not  quarreling 
with  the  fact  that  you're  performing  the  test.  I  am  trying  to  ad- 
dress the  reporting,  the  disclosure  and  the  information  which  is 
given  to  the  women  who  are  involved  in  the  particular  test. 

We've  talked  here  about  reports  with  regard  to  treatment  and 
with  regard  to  prevention.  But  I'm  trying  to  find  out  the  reports 
that  you  have  received  in  each  instance  and  the  reports  that  the 
women  who  are  involved  in  these  programs  are  receiving.  I  sense 
that  they  may  be  getting  certain  reports  in  connection  with  the 
treatment  program,  but  they  may  not  be  getting  it  in  connection 
with  the  prevention  tests  which  are  going  on. 

Now,  am  I  fair  in  that  inference  or  not? 

Mr.  Broder.  Yes,  you  are.  You  are  fair  and  within  24  hours  we 
will  give  you  a  report  of  the  status  of  what  our  information  flow 
has  been. 

Mr.  DiNGELL.  That  would  be  very  helpful.  My  time  has  expired 
and  I  want  to  recognize  my  good  friend  and  I'm  going  to  apologize 
to  him  right  now,  but  there's  a  question  that  we  have  not  gotten 
an  answer  on.  We  do  not  now  know  whether  the  women  have  re- 
ceived the  necessary  notification  of  either  the  new  risks,  the  new 
circumstances,  or  the  failure  to  adequately  inform  them. 

We  do  not  know  yet  whether  or  not  you  have  in  your  rules  and 
regulations  and  in  the  protocols  the  requirement  that  kind  of  infor- 
mation be  made  available.  We  do  not  know  whether  that  kind  of 
information  has,  in  fact,  been  made  available  and  whether  there  is 
a  policy  change  needed  at  NIH  to  see  to  it  that  this  notification 
goes  forward  to  the  people  who  have  been  put  at  additional  risk  be- 
cause of  the  kind  of  situation  we  find  in  the  tamoxifen  tests. 

Can  you  tell  us  whether  or  not  you  have  requirements  in  the  pro- 
tocol, either  at  NIH  generally  or  at  NCI,  which  requires  that  this 
new  information  be  made  available  to  the  persons  who  were  in- 
volved as  it  comes  available? 


65 

The  problem  we  have  here  is  women  are  at  risk.  Women  are  sub- 
ject to  potentially  higher  levels  of  risk  of  cancer,  uterine  cancer,  in 
connection  with  it.  We  also  want  to  know  whether  they  are  able, 
then,  to  monitor  their  own  affairs  more  fully  and  carefully  because 
they  have  the  risk  that  they  can  take  to  their  own  doctors  or  that 
can  be  made  available  to  the  researchers  who  might  be  working 
with  them  at  the  different  sites. 

Can  you  address  those  questions,  please? 

Mr.  Varmus.  Mr.  Chairman,  let  me  see  if  I  can  help  with  this. 
Under  the  Office  of  Protection  from  Research  Risks,  we  have  rules 
that  dictate  that  information  that  concerns  adverse  outcomes  or  ad- 
verse effects  of  instruments  used  in  clinical  trials  or  prevention 
trials  be  communicated  to  the  institutional  review  boards  at  the 
sites  at  which  these  studies  are  being  conducted. 

Mr.  DiNGELL.  That's  to  the  people  at  the  site. 

Mr.  Varmus.  Let  me  finish,  please.  At  those  sites  are  found  the 
names  and  addresses  of  study  participants.  We  do  not  have  at  NIH 
the  names  and  addresses  of  participants. 

Mr.  DiNGELL.  I'm  not  critical  of  NIH  with  regard  to  your  inability 
to  notify  these  people.  I  am  trjdng  to  find  out  whether  you  have  a 
situation  which  does  require  the  necessary  notification. 

Mr.  Varmus.  It  is  a  regulation  that  all  patients  in  the  study  be 
informed  through  the  institutional  review  boards.  You're  raising  a 
legitimate  question  of  whether  we  should  have  tougher  rules  to  fol- 
low-up on  the  notification  process.  You  can  rest  assured  that  we 
will  be  looking  into  that  very  vigorously. 

Mr.  Broder.  I'd  like  to  second  that,  because  I  want  to  assure  you 
that  we  take  your  concerns  and  criticisms  very  seriously  and  to 
heart.  I  believe  they  are  valid.  We  will  look  to  see  whether  there 
is  a  structural  problem  that  we  can  repair.  We  will  also  explore, 
although  I  cannot  promise  you  today,  whether  at  least  the  NCI  has 
some  right  of  direct  access  to  patients.  I  believe  that  we  will  prob- 
ably be  told  that  we  have  limited  access. 

Mr.  DiNGELL.  I  think  it  would  be  useful  if  you  had  direct  access, 
but  I  think  it's  even  more  useful  if  you  could  simply  require  that 
the  patients  do  be  informed. 

Mr.  Broder.  That  is  done. 

Mr.  Varmus.  We  do  require  that. 

Mr.  Broder.  That  is  required. 

Mr.  Varmus.  But  you're  asking  whether  I  know  that  all  the  pa- 
tients have  been  informed  and  I  cannot  say  that  I  know  that. 

Mr.  Broder.  Also,  we  have  limited  rights  of  asking  a  grantee  to 
provide  names  and  addresses,  but  we  will  certainly  try  to  review 
that,  as  well. 

Mr.  DiNGELL.  The  deaths  should  also  have  been  reported  in  1992 
before  any  of  the  patients  entered  the  prevention  study,  should 
they  not? 

Mr.  Broder.  That's  correct. 

Mr.  DiNGELL.  That  was  not  done. 

Mr.  Broder.  That  was  not  done.  As  far  as  I  can  tell,  it  was  not 
done  even  to  the  FDA. 

Mr.  DiNGELL.  Can  you  tell  us  why? 

Mr.  Broder.  I  would  have  to  speak  for  Dr.  Fisher  and  I  would 
prefer  not  to  do  that. 


66 

Mr.  DiNGELL.  Well,  it  might  be  a  little  bit  difficult.  As  the  record 
shows,  we  have  invited  Dr.  Fisher  to  appear  here  and  he  has  indi- 
cated that  his  health  prevents  him  from  being  with  us.  We  perhaps 
will  be  affording  him  another  opportunity,  but  as  I  have  indicated, 
we  are  going  to  be  asking  the  university  to  come  forward. 

Mr.  Broder.  I  hope  his  health  improves. 

Mr.  DiNGELL.  Pardon? 

Mr.  Broder.  I  hope  his  health  improves. 

Mr.  DiNGELL.  I  do,  too.  At  least  enough  that  he  can  appear  here 
before  us.  Well,  the  Chair  has  used  more  time  than  I  am  entitled 
to.  The  Chair  recognizes  the  gentleman  from  Colorado,  Mr.  Schae- 
fer. 

Mr.  Schaefer.  Dr.  Broder,  the  NCI  issued  a  statement  on  March 
14  of  1994  that  I  would  want  to  read  for  the  record.  I'm  sure  you're 
familiar  with  it.  Its  headline  is  "National  Cancer  Institute's  State- 
ment on  Breast  Cancer  Treatment  Studies." 

The  original  conclusion  reads  as  follows.  "Following  evidence  that 
fraudulent  data  has  been  submitted  as  part  of  large  breast  cancer 
treatment  group  trials,  the  scientists  overseeing  the  trials  and  staff 
of  the  National  Cancer  Institute  reanalyzed  the  data.  The  re-ana- 
lyzation  was  done  without  any  of  the  data  supplied  by  the  inves- 
tigator accused  of  fraud  and  that  reanalysis  using  data  exclusively 
from  other  institutions  participating  in  the  group  reaffirmed  origi- 
nal results." 

Was  this  a  true  statement  when  it  was  issued? 

Mr.  Broder.  I  believe  it  was  substantively  correct.  There  are 
many  issues  about  what  the  word  "reanalysis"  meant.  But  there 
was  in  hand  at  that  point  a  report  from  the  NSABP  which  had  cer- 
tain issues  of  discussion,  but  which  substantively  confirmed  the 
end  points  and  did  remove  the  fraudulent  data  site. 

Mr.  Schaefer.  Did  the  NCI  analyze  this  data? 

Mr.  Broder.  The  NCI  did  not  analyze  the  data.  The  people 
overseeing  the  study  that  I  believe  you  read  were  the  people  from 
the  NSABP,  the  principal  investigator.  The  NCI  analyzed  the  data 
from  the  standpoint  that  our  statistician,  a  government  statistician 
who  critically  reviewed  the  report,  made  suggestions  that  were 
transmitted  back  to  the  NSABP,  but,  in  fact,  did  feel  that  the  sub- 
stantive issues  were  valid,  that  the  substantive  end  points  were 
valid. 

Mr.  Schaefer.  But  NCI  was  forced  to  retract  the  statement  after 
it  was  released.  Is  that  correct? 

Mr.  Broder.  It  became  a  definitional  term  about  the  word  "ana- 
lyze." I  believe  that  people  of  goodwill  can  use  that  term  in  mul- 
tiple ways.  We  understand  that  term  had  a  special  meaning  and 
when  individuals  meant  the  term  "reanalyze",  they  wanted  us  to  be 
the  individuals  to  reanalyze  it. 

I'm  sorry  for  the  confusion.  It  will  not  happen  again. 

Mr.  Schaefer.  What  about  the  ordinary  people  who  were  in- 
volved in  reading  it?  Did  they  understand  this  stuff? 

Mr.  Broder.  The  word  "analysis"  is  open  to  multiple  interpreta- 
tions. One  can  analyze  a  scientific  experiment  or  analyze  some- 
body's argument  or  analyze  a  problem  without  necessarily  doing 
the  firsthand  work  oneself  One  looks  at  the  work  product  and  then 
analyzes  it.  That  was  the  use  of  that  term. 


67 

We're  sorry  if  there  is  confusion  on  that  point,  but  we  do  have 
our  own  analyses  which  have  been  provided  to  the  committee.  So 
any  doubt  or  ambiguity  on  this  point  has  now  been  laid  to  rest. 

Mr.  SCHAEFER.  Let  me  ask  you  this  question.  How  many  people 
received  this  erroneous  statement? 

Mr.  Broder.  Sir,  with  respect,  this  is  open  to  different  interpre- 
tations. If  you  believe  the  statement  was  erroneous,  I  will  accept 
your  point.  But  I  believe  the  term  "analyze"  is  open  to  multiple  in- 
terpretations. 

Mr.  SCHAEFER.  But  you  still  had  to  retract  it  and  then  reanalyze 
it,  didn't  you? 

Mr.  Broder.  But  we  have  the  reanalysis,  sir.  It's  been  provided. 
Our  own  analysis  of  the  relevant  studies  has  been  provided  to  the 
committee.  It  is  on  Internet,  it  is  on  our  electronic  databases.  It  has 
been  sent  to  members  of  the  National  Cancer  Advisory  Board.  It's 
been  sent  to  Kay  Dickerson,  it's  been  sent  to  Fran  Visco  and  so  on. 

These  are  our  own  analyses,  not  the  NSABP.  We  have  distrib- 
uted this  and  we  are  sorry  that  there  mav  have 

Mr.  Schaefer.  This  is  an  updated  analysis  now. 

Mr.  Broder.  No.  It  is  our  work.  We  asked  for  and  demanded  the 
original  computer  data  files,  something  which  is  done  extremely 
rarely.  It  will  be  more  common  in  the  future.  But  we  asked  for  and 
were  provided  the  original  data  files.  We  are  also  doing  chart  au- 
dits, which  is  different  from  the  computer  data  files.  But  those  doc- 
uments have  been  provided.  I  can  provide  them  to  you  now,  if  you 
will  permit  me  to  put  them  into  the  record.  I  have  them  with  me. 

Mr.  DiNGELL.  Without  objection,  so  ordered. 

[The  documents  referred  to  are  retained  in  subcommittee  files.] 

Mr.  Broder.  With  the  Chair's  permission,  I  will  provide  you  with 
the  documents  as  they  are  being  distributed. 

Mr.  Schaefer.  I  really  want  to  get  down  to  this  point.  The  first 
statement  was  issued.  It  was  retracted,  or  it  was  redone  or 
reanalyzed.  What  was  it?  There  was  a  difference,  right?  So,  there- 
fore, people  read  the  first  statement  and  how  did  they 

Mr.  Broder.  And  they're  true  and  they  say  different  aspects  of 
it.  In  the  early  portion  of  February,  we  received  an  NSABP  report 
which  analyzed,  statistically  analyzed  the  end  points  of  the  various 
studies  affected  by  the  fraudulent  data  site,  with  and  without  the 
data  site  from  the  fraudulent  site  in  the  report. 

With  the  Chair's  and  the  committee's  indulgence,  I  have  to  intro- 
duce a  term.  They  analyzed  it  by  intent  to  treat,  which  is  a  valid 
way,  but  did  create  some  confusion.  I  can  define  that  term  now  or 
I  can  define  it  to  you  for  the  record. 

But  it  does  provide  a  valid  way  of  analyzing  material.  That  was 
reviewed  by  our  in-house  staff  and  it  was  reviewed  by  Dr.  Simon, 
who  raised  certain  criticisms,  constructive  criticisms  that  were  pro- 
vided. But  the  conclusion  was  that  the  Poisson  data  removal  did 
not  change  any  of  the  major  end  points.  In  fact,  the  studies  basi- 
cally, in  most  of  the  major  things  that  we  discussed,  were  the 
same. 

We  have,  in  addition  to  that,  demanded  the  original  computer 
data  files  and  have  run  with  our  own  agents  a  reanalysis  independ- 
ently down  here  in  Bethesda.  Those  reports  are  with  me  today  and 
I  will  be  glad  to  submit  them  to  you  for  the  record.  They  have  al- 


68 

ready  been  circulated.  They  are,  as  we  speak,  being  circulated. 
They  are  on  Internet.  They  are  available  by  our — anyone  who  has 
a  computer  service  can  download  this  through  our  PDQ  system  and 
so  on. 

So  what  I'm  trying  to  say  to  you  is  that  this  process  has  more 
closure  than  perhaps — it's  called  the  EMMES  analysis  because  this 
is  a  private,  highly  sophisticated,  statistical  firm  that's  a  contractor 
that  reports  to  us.  They  did  everything  from  the  computer  data 
files. 

We  also  are  auditing  the  various  sites  with  our  own  government 
workers  or  contractors  that  report  to  us.  Dr.  Friedman  is  prepared 
to  provide  you  with  the  audit  summaries  as  to  where  we  are  today. 

So  I  apologize  if  the  term  "analyze"  had  some  confusion,  but  to 
those  of  us  in  the  scientific  community,  the  word  "analysis"  or 
"analyze"  has  multiple  interpretations.  But  all  interpretations  of 
that  term  have  been  resolved  as  we  speak  today. 

Mr.  SCHAEFER.  Let  me  ask  you  this  question.  Did  the  reanalysis 
review  all  the  points  in  the  same  manner  as  the  original  analysis? 

Mr.  Broder.  It  did  it  both  as  to  the  original  analysis,  but  be- 
cause we  had  possession  of  the  computer  data  file,  we  were  able 
to  ask  and  clarify  questions  that  individuals  have  raised;  for  exam- 
ple, the  ipsolateral  breast  cancer  story  we  could  address  and  we 
could  do  certain  kinds  of  analyses  that  were  not  even  in  the  origi- 
nal publications. 

So  the  answer  is,  yes,  we  did  and  we  did  more.  So  there  is  a 
value-added  function  in  looking  at  the  reports  that  we  have  and  the 
reader  will  be  able  to  get  more  information. 

We  also  have  a  copy  of  the  New  England  Journal  of  Medicine 
submittal  which  we  compelled  Dr.  Fisher  to  submit.  I  have  pro- 
vided a  copy  of  that  New  England  Journal  paper  to  the  committee 
and  would  be  prepared  to  distribute  it  to  any  members  of  the  com- 
mittee who  wish  to  have  it.  If  the  committee  advises  us  to,  we  will 
make  the  New  England  Journal  submittal  public,  as  well. 

Mr.  SCHAEFER.  Who  was  responsible  for  releasing  this  statement 
in  the  first  place? 

Mr.  Broder.  This  was  probably  coordinated  through  our  Office 
of  Cancer  Communication.  I  will  accept  responsibility  for  this  and 
any  other  matters  that  the  committee  feels  needs  to  be  accounted. 

Mr.  SCHAEFER.  We  did  a  re-analysis  and  I  just  want  to  say  that 
for  the  common  lay  person  out  there,  who  may  not  understand  sci- 
entific terms,  that  we  would  do  well  in  the  future  to  make  sure 
that  whatever  is  conveyed  to  these  individuals,  is  not  going  way 
over  their  heads.  They'll  know  exactly  what  was  talked  about. 

Mr.  Broder.  Sir,  these  will  be  the  documents  that  will  be  sub- 
mitted so  that  they  can  be  identified.  These  are  the  documents  that 
we  have  done.  I  have  with  me  here  a  copy  of  Dr.  Fisher's  New  Eng- 
land Journal  of  Medicine  paper. 

What  I  would  like  to  advise  the  committee  is  that  we  have  addi- 
tional analyses  in  our  preparations,  looking  at  different  data  points 
and  different  ways  of  looking  at  the  data,  that  actually  are  not 
even  considered  in  this  paper.  Dr.  Fisher's  paper.  But  the  bottom 
line  is  that  we  have  looked  at  all  of  the  end  points  that  we  know 
how  to  look  at  and  including  some  that  he  has  not  published. 


69 

Mr.  SCHAEFER.  Would  you  then  say  that  the  three  ladies  that  we 
had  here  prior  to  this  panel,  that  they  would  take  those  and  could 
understand  them? 

Mr.  Broder.  I  believe  so.  I  believe  the  panel  was  composed  of  ex- 
tremely intelligent  women  who  have  asked  good  questions  and  who 
understand  the  facts  and  are  among  the  most  tragic  aspects  of  this 
issue.  Basically,  we  need  to  understand  at  the  National  Cancer  In- 
stitute that  we  report  to  the  first  panel  and  not  to  Dr.  Fisher. 

Mr.  ScHAEFER.  Mr.  Chairman,  I'm  over  my  time  here.  I  have  a 
couple  other  questions. 

Mr.  DiNGELL.  The  Chair  will  recognize  you  further. 

Mr.  SCHAEFER.  Dr.  Friedman,  you  were  responsible  for 
overseeing  and  monitaring  the  reports  that  came  in  from  the  Uni- 
versity of  Pittsburgh,  is  that  correct? 

Mr.  Friedman.  Yes,  sir. 

Mr.  SCHAEFER.  How  many  people  were  assigned  to  this  specific 
oversight? 

Mr.  Friedman.  There  were  two  people  at  that  time  in  the  audit- 
ing section.  Neither  one  was  devoted  specifically  to  the  University 
of  Pittsburgh.  Both  had  responsibility  for  auditing  and  quality  as- 
surance oversight. 

Mr.  SCHAEFER.  Is  this  an  adequate  number  to  correctly  do  it? 

Mr.  Friedman.  I  think  the  problem  was  not  so  much  the  num- 
bers as  the  procedures  and  the  ability  that  we  exercised  in  having 
what  Dr.  Broder  has  described  as  constructive  criticism  actually 
translated  into  meaningful  action. 

Mr.  Schaefer.  How  can  we  assure  that  reports  now  coming  from 
the  University  of  Pittsburgh  are  being  adequately  monitored?  Are 
you  investigating  whether  you're  going  to  use  more  people  or  not? 

Mr.  Friedman.  Sir,  there  are  a  number  of  answers  to  that  ques- 
tion and  I  will  be  happy  to  give  you  the  various  aspects  of  it  and 
then  ask  Dr.  Broder  or  Dr.  Chabner  to  supplement  anything  that 
I  have  left  out. 

First  of  all,  the  entire  way  in  which  business  is  conducted,  re- 
search business  and  quality  assurance  business  at  the  University 
of  Pittsburgh  and  the  National  Surgical  Adjunct  Program,  has  been 
changed.  The  laxness,  the  imprecision  which  characterized  some  of 
their  administrative  activities  in  the  past  no  longer  is  allowed  to 
exist  today. 

So  that  they  must  provide  to  us  and  have  provided  to  us  a  com- 
plete auditing  schedule.  They  understand  what  their  requirements 
are  for  reporting  things  to  us  in  a  timely  way.  By  that,  I  mean  they 
must  report  to  us  within  24  hours  after  an  audit  is  conducted.  We 
must  have  within  6  weeks  a  written  report  of  that  audit. 

Mr.  Schaefer.  When  was  all  this  changed? 

Mr.  Friedman.  Sir,  these  were  new — when  the  University  of 
Pittsburgh  and  this  group  were  put  on  probation  at  the  very  end 
of  March,  a  whole  series  of  instructions  were  provided  to  them  and 
those  are  the  features  that  I'm  speaking  about,  sir. 

Mr.  Schaefer.  So  we  had  to  have  an  issue  like  this  come  out  be- 
fore you  were  moving  to  do  new  things  on  adequately  monitoring 
this  information. 

Mr.  Friedman.  Sir,  the  numerous  times  that  we  contacted 

Mr.  Schaefer.  We're  dealing  with  a  lot  of  women's  lives  here. 


70 

Mr.  Friedman.  I'm  sorry,  sir.  I  didn't  hear  you. 

Mr.  SCHAEFER.  We're  dealing  with  a  lot  of  women's  lives  in  this 
country. 

Mr.  Friedman.  The  subject  is  enormously  important.  The  quality 
of  these  data,  the  trust  with  which  the  public  holds  these  data  are 
terribly  important.  Our  ability  to  compel  Dr.  Fisher,  our  ability  to 
institute  changes  that  we  had  recommended  did  not  occur  until 
very  recently. 

Mr.  Schaefer.  So  you  had  recommended  these  changes  prior  to 
these  statements  and  the  studies  being  issued? 

Mr.  Friedman.  Yes,  sir,  we  had. 

Mr.  Schaefer.  And  it  was  stonewalled.  In  other  words,  nothing 
was  done. 

Mr.  Broder.  I  believe  the  correct  answer  is  that  Dr.  Fisher, 
maybe  not  directly,  but,  in  effect,  told  us  by  implication  that  he's 
been  doing  clinical  trials  a  long  time,  perhaps  before  we  were  out 
of  school.  He  knows  what  to  do.  He's  been  doing  things  since  the 
late  1950's  and  he  knows  how  to  get  the  job  done. 

No  one  will  ever  tell  us  that  again.  We  will  do  what  we  have  to 
do.  Our  staff  understands  the  mission.  They  understand  what  we 
need  to  do.  I  believe  that  Dr.  Fisher  has  made  a  number  of  accom- 
plishments and  I  believe  his  accomplishments  have  benefited 
women  to  an  extremely  high  degree.  That's  not  the  issue  here 
today. 

The  issue  here  is  that  no  one  is  above  our  rules  and  we  will  see 
to  it. 

Mr.  Schaefer.  Well,  I  think  that's  something  that  the  chairman 
and  I  are  very  pleased  to  hear.  If  I  might  ask  one  more  question, 
Mr.  Chairman. 

Mr.  DiNGELL.  The  gentleman  continues  to  be  recognized. 

Mr.  Schaefer.  Dr.  Broder,  did  any  officials  at  NCI  notify  the  edi- 
tor of  the  New  England  Journal  of  Medicine  that  the  St.  Luc  data 
was  in  doubt? 

Mr.  Broder.  No,  they  did  not,  until  very  recently. 

Mr.  Schaefer.  Why  weren't  scientific  journals  notified? 

Mr.  Broder.  Because  it  was  the  mistaken  belief  that  the  primary 
obligation  should  be  with  the  person  who  authored  the  words.  I 
still  hold  to  that  principle.  The  person  who  authors  a  paper  has  the 
primary  duty  to  retract  and  correct  that  paper,  irrespective  of  what 
a  government  agency  does. 

So  even  though  we  are  changing  and  I  will  provide  you  with  a 
different  point  of  view,  I  still  think  that  responsibility  should  not 
be  lost  sight  of  The  primary  duty  for  correcting  a  paper  lies  with 
the  primary  investigator  who  wrote  the  original  paper. 

The  belief,  I  believe,  was  that  Dr.  Fisher  was  extremely  pre- 
eminent, extremely  experienced,  knew  what  he  was  doing.  In  addi- 
tion, there  was  some  inhibition  and  self-consciousness  about  order- 
ing him  to  do  anything. 

The  other  issue  is  that  it  would  have  been  best  for  all  parties  had 
there  been  a  simultaneous  process  in  which  Dr.  Fisher  and  our 
group  cooperated  in  revealing  all  of  the  facts  as  promptly  as  pos- 
sible. It  becomes  difficult  and  awkward  for  the  NCI  to  act  alone 
without  the  investigator  cooperating  with  us. 


71 

However,  that  will  not  happen  again.  We  will  have  in  place  a  pol- 
icy in  which  these  things  occur  promptly,  even  possibly  and  likely, 
in  fact,  in  a  clinical  trial  before  the  ORI  investigation  is  over,  and 
we  have  proven  that.  You  have  a  press  release  today,  I  understand 
from  Dr.  Bivens. 

Mr.  SCHAEFER.  What  is  the  press  release?  What  does  it  deal 
with? 

Mr.  Broder.  Dr.  Bivens? 

Mr.  ScHAEFER.  You're  saying  you're  going  to  change  the  way 
you're  doing 

Mr.  Broder.  No,  no,  no.  It's  a  substantive  press  release. 

Mr.  Bivens.  I  don't  know  if  it  has  been  released  or  not. 

Mr.  Broder.  The  press  release  is  being  released  today  on  a  sec- 
ond case  of  fraud  at 

Mr.  Schaefer.  A  second  case. 

Mr.  Broder.  Yes,  at  another  hospital  in  Montreal. 

Mr.  Schaefer.  Dealing  with  breast  cancer? 

Mr.  Broder.  That's  correct. 

Mr.  Schaefer.  Or  something  else? 

Mr.  Broder.  Dealing  with  breast  cancer. 

Mr.  Schaefer.  Well,  just  briefly  tell  me  and  Mr.  Chairman  here 
what  this  press  release  says. 

Mr.  Broder.  I  believe  the  facts  have  been  provided  to  the  com- 
mittee. 

Mr.  Schaefer.  Do  we  have  that? 

Mr.  Dingell.  There  was  a  comment,  I  believe,  in  Dr.  Broder's 
prepared  testimony  on  this  particular  matter. 

Mr.  Broder.  I  addressed  this  point  in  my  opening  statement. 

Mr.  Varmus.  This  matter  has  been  reported  in  the  press  pre- 
viously. There  have  been  allegations  of  irregularities  or  there  have 
been  irregularities  detected  in  recordkeeping  in  St.  Mary's  Hospital 
in  Montreal. 

Mr.  Dingell.  Did  that  also  involve  Dr.  Poisson? 

Mr.  Varmus.  No,  it  did  not. 

Mr.  Dingell.  A  different  doctor. 

Mr.  Varmus.  It  was  a  different  case.  It  was  a  case  that  was  most 
recently  described  in  the  press  after  the  NCI  visited  the  NSABP 
Center  in  Pittsburgh.  The  case  was  reported  to  the  Office  of  Re- 
search Integrity  and  that  office  is  investigating  the  nature  of  the 
irregularities  and  determining  whether  or  not  they  constitute  sci- 
entific misconduct. 

Mr.  Broder.  But  Dr.  Fisher  was  removed  within  days  of  the  de- 
tection of  the  second  issue.  I  apologize  if  my  opening  statement  did 
not  clarify  all  the  facts,  but  I  did  try  to  address  them  in  my  open- 
ing statement  and  would  be  happy  to  provide  more  information. 

Mr.  Dingell.  I  think  more  information  on  this  matter  would  be 
useful,  Doctor,  and  we'd  appreciate  that,  for  the  record.  The  gen- 
tleman from  Colorado  continues  to  be  recognized. 

Mr.  Schaefer.  I  thank  the  Chair.  Dr.  Bivens,  I  noticed  that  Dr. 
Poisson  was  prohibited  from  serving  on  the  Public  Health  Advisory 
Committee  and  was  barred  from  receiving  Federal  funds  or  grants 
for  a  period  of  8  years.  Is  this  a  maximum  debarment? 

Mr.  Bivens.  It's  very  close  to  the  maximum  debarment  that  the 
Department  imposes. 


72 

Mr.  SCHAEFER.  What  is  the  maximum? 

Mr.  BiVENS.  The  longest  one  I  know  of  is  10  years.  There  may 
be  longer  ones,  but  the  only  one  I'm  familiar  with,  which  is  longer 
than  8  years,  is  another  scientific  misconduct  case.  The  modal  term 
for  debarments  across  the  Department  is  on  the  order  of  3  years. 
So  anything  in  excess  of  3  years  we  have  to  make  an  especially 
strong  case  for  to  the  debarring  official. 

Mr.  SCHAEFER.  Is  that  regulation? 

Mr.  Bivens.  I  don't  know  that  the  term  of  debarment  is  written 
into  the  regulation,  no,  sir.  But  it's  a  practice  that  the  Assistant 
Secretary  for  Management  and  Budget  applies,  in  which  3  years  is 
the  usual.  If  there  are  more  serious  offenses,  it  can  be  longer.  I 
can't  say  much  more  than  that  because  I  don't  want  to  speak  for 
the  Assistant  Secretary  for  Management  and  Budget. 

Mr.  SCHAEFER.  I  guess  the  question  I  have  is  that  if  somebody 
is  guilty  of  fraud,  why  should  they  ever,  ever  be  eligible  to  receive 
Federal  grants? 

Mr.  Bivens.  That's  a  perfectly  legitimate  question.  I  think  in 
some  cases,  they  should  never  be  eligible  to  receive  grants.  I  guess 
I  would  be  surprised  of  Dr.  Poisson  ever  came  in  for  an  NIH  appli- 
cation in  the  foreseeable  future.  But,  nevertheless,  I'm  stuck  with 
the  practice  of  the  Department  and  the  standard  terms  of  debar- 
ment. We  have  to  argue  quite  strongly  for  debarments  in  excess  of 
3  years. 

It  is  certainly  arguable  that  8  years  is  insufficient. 

Mr.  SCHAEFER.  I  would  certainly  agree  with  that.  I  will  yield  to 
my  friend  here  for  a  minute.  Let  me  regroup  and  see  what  else  I've 
got  here. 

Mr.  DiNGELL.  I  want  to  come  back  to  the  question.  You  had  two 
studies  here  and  we  dealt  with  the  question  of  notification.  We 
have  talked  of  the  prevention  study,  but  we  have  not  talked  to  the 
treatment  study. 

On  the  treatment  study,  has  there  been  any  notification  either 
of  NIH  or  of  the  participants  in  the  study  with  regard  to  the  possi- 
bility of  increased  risk  of  uterine  cancer? 

Mr.  Broder.  With  the  Chair's  permission,  I'd  like  Dr.  Chabner 
to  address  that. 

Mr.  DiNGELL.  Can  you  help  us  out  with  that,  please,  Doctor? 

Mr.  Chabner.  May  I  address  that,  sir? 

Mr.  DiNGELL.  Certainly. 

Mr.  Chabner.  Yes.  On  January  12,  we  issued  new  information 
to  all  of  the  treatment  centers  to  inform  them  that  informed  con- 
sents must  be  changed  to  reflect  new  appreciations  of  what  the 
risks  of  endometrial  cancer  were  and  the  fact  that  we  had  just 
learned  that  deaths  had  been  reported. 

Mr.  DiNGELL.  Was  that  done,  do  you  know? 

Mr.  Chabner.  I  do,  sir,  because 

Mr.  DiNGELL.  Was  it  done  by  the  centers? 

Mr.  Chabner.  Yes,  sir.  I've  gotten  information  back  from  our  co- 
operative groups  who  participate  in  these — who  sponsor  and  direct 
these  studies  that  the  amendments  have  been  changed;  that  is,  the 
informed  consent  documents  have  been  changed  for  all  the  studies 
and  that  patients  are  being  informed  at  this  moment. 


73 

If  I  may  point  out,  sir,  some  of  the  studies  already  had  within 
them  the  risk  of  death  and  they  had  within  them  descriptions  of 
endometrial  cancer  risks.  So  what  we're  doing  is  making  sure  all 
the  studies  come  up  to  a  certain  standard. 

These  studies  are  slightly  different  than  the  prevention  trials, 
sir,  in  that  this  is  the  commercially-available  use  of  this  agent;  that 
is,  tamoxifen  is  commercially-available  and  many  thousands  of 
women  take  it.  So  we  are  trying  to  have  our  informed  consent  docu- 
ments measure  up  to  the  latest  information  that  we  get  from  the 
drug  company,  as  well. 

Mr.  DiNGELL.  I  applaud  this.  We've  come  back  to  the  prevention 
study  that  we  have  not  been  discussing  at  this  minute.  We  still 
confront  the  problem  that  we  don't  know  what  has  happened  with 
regard  to  the  women  who  are  participants  in  that  study  in  terms 
of  upgrading  the  notice  that  they  had  of  potential  risks.  Is  that 
right? 

Mr.  Chabner.  Sir,  my  understanding  is  that  at  all  the  sites,  in- 
formation is  provided  for  both  the  prevention  trial  and  the  treat- 
ment trial.  Just  as  others  have  said,  I  cannot  assure  you  today  that 
every  last  woman  has  been  informed. 

Mr.  DiNGELL.  I  accept  that  and  I  don't  want  you  to  feel  I'm  inter- 
rupting you.  I'm  satisfied  with  your  answer.  But  we  then  confront 
the  little  additional  difficulty  that  we  don't  know  yet  what  the  re- 
quirements are  with  regard  to  warnings  to  participants  in  the  stud- 
ies. 

Am  I  fair  in  that  appreciation.  Dr.  Varmus  or  Dr.  Broder? 

Mr.  Varmus.  We  do  require  that  they  be  informed.  But  you  are 
asking  whether  we  know  that  everybody  has  been  informed  and  we 
do  not  know  that. 

Mr.  DiNGELL.  But  what's  in  the  protocols  with  regard  to  inform- 
ing participants  in  these  studies  about  changes  in  circumstances; 
in  other  words,  additional  risks  that  might  become  known  as  the 
process  goes  forward?  Do  you  have  some  kind  of  a  generic  policy 
with  regard  to  that  or  do  you  not? 

Mr.  Broder.  While  they're  looking  for  the  documents,  I  will 
speak  for  the  NCI.  There  is  a  requirement  that  institutions,  as  part 
of  their  human  subjects  assurance,  a  broader  policy  than  the  NCI, 
must  have  a  process  for  informing  patients  about  research  risks 
and  benefits,  that  they  must  have  an  institutional  review  board 
that  must  approve  such  changes,  and  that  they  will  update  and 
bring  new  information  both  to  the  institutional  review  board  and 
to  the  patients  as  new  facts  become  available. 

Mr.  DiNGELL.  So  we  would  have  a  problem,  then,  if  that  kind  of 
notice  had  not  been  given  to  the  women  who  were  participating  in 
the  studies. 

Mr.  Broder.  We  have  a  problem  whenever  information  flow  is 
blocked. 

Mr.  DiNGELL.  Could  you  check  and  find  out  for  us,  please,  gentle- 
men, whether  or  not  the  information  on  these  matters  has  flowed 
through  in  compliance  with  the  regulations  at  NCI? 

Mr.  Broder.  I  will  give  you  a  status  report  within  24  hours. 

Mr.  DiNGELL.  It  doesn't  have  to  be  24  hours.  Just  at  your  earliest 
comfortable  convenience.  We're  speaking  here  as  friends,  we  want 
you  to  understand. 


74 

Mr.  Broder.  We  appreciate  that. 

Mr.  DiNGELL.  This  to  Dr.  Varmus.  Doctor,  how  seriously  do  you 
view  the  withholding  of  information  about  tamoxifen-related  deaths 
by  one  of  NCI's  largest  grantees  and  one  of  the  largest  grantees 
from  the  FDA  and  potential  withholding  of  information  from  NCI, 
potential  withholding  of  information  from  FDA,  and  from  the 
American  public?  Is  this  a  serious  matter  or  not? 

Mr.  Varmus.  Of  course,  it's  a  serious  matter,  extremely  serious. 

Mr.  DiNGELL.  Are  you  concerned? 

Mr.  Varmus.  Of  course,  I'm  concerned. 

Mr.  DiNGELL.  Figure  we  maybe  ought  to  take  a  look  at  the  rules 
and  regulations  and  see  whether  they're  inadequate? 

Mr.  Varmus.  The  regulations  with  respect  to  the  reporting  of  in- 
formation to  us,  I  think,  is  unequivocal.  What  we're  trying  to  estab- 
lish here,  because  you've  raised  an  interesting  question,  is  the  reg- 
ulations as  they  pertain  to  our  assurance  that  any  individuals  en- 
gaged in  any  clinical  research  studies  be  informed  through  the  con- 
sent form  of  any  changes  in  our  information. 

There  is,  it  appears,  still  a  degree  of  local  autonomy  with  respect 
to  how  the  consent  forms  are  constituted.  We  are  obligated  to  in- 
form the  institutional  review  boards  of  any  new  information  that 
is  pertinent  to  the  writing  of  the  consent  form.  It  is  then  in  the  ju- 
risdiction of  that  institutional  review  board  to  review  the  informa- 
tion and  to  make  a  decision  about  how  they're  going  to  change  the 
form. 

The  form  must  then  be  returned  to  us  so  that  we  can  review  it 
and  advise  them.  But  you've  raised  a  question  that  is  new  to  me, 
frankly,  with  respect  to  the  degree  to  which  we  can  impose  our  will 
upon  the  rewriting  of  a  consent  form  in  response  to  new  informa- 
tion. There  is,  at  the  moment,  some  autonomy  accorded  to  the  local 
institutional  review  boards. 

Mr.  DiNGELL.  Let's  get  down  to  a  document  that  has  just  fallen 
into  the  hands  of  the  committee.  Yesterday  afternoon,  Zeneca  Phar- 
maceuticals produced  a  number  of  documents  to  the  subcommittee 
regrading  their  knowledge  of  cancers  and  deaths  associated  with 
the  B-14  trial.  One  such  document  is  an  internal  Zeneca  memoran- 
dum, dated  July  7,  1993.  I'm  going  to  quote  from  parts  of  it  here. 

It  says  as  follows,  and  I'm  quoting,  "I  then  proceeded  to  tell  Dr. 
Fisher  that  the  increasing  number  of  patients  within  the  B-14  trial 
developing  endometrial  cancer  while  on  Nolvadex  did  prompt  us  to 
look  at  this  issue  more  closely.  Upon  careful  review  of  the  data,  we 
felt  that  there  was  an  increased  risk  to  develop  endometrial  cancer 
with  Nolvadex  and  that  we  will  modify  our  label  to  reflect  this.  I 
also  commented  that  it  was  impossible  to  precisely  quantitate  the 
relative  risk,  although,  qualitatively,  it  did  appear  that  there  was 
a  slight  increase  incidence." 

"Dr.  Fisher  agreed  with  this  assessment  and  felt  that  we  were 
acting  responsible",  and  that's  a  direct  quote,  "by  changing  our 
label.  I  commented  to  him  that  at  least  in  the  United  States  we 
would  have  to  make  minor  changes  in  our  label,  but  I  did  not  see 
these  changes  having  a  great  impact  on  the  treatment  of  patients 
with  confirmed  breast  cancer,  and  also  on  the  U.S.  prevention  trial, 
since  the  protocol  did  include  the  B-14  data,  as  well  as  the  Swedish 
data,  and  that  this  potential  risk  was  noted  on  the  consent  form." 


75 

"However,  I  did  comment  that  it  did  have  more  of  an  impact  on 
the  European  trial,  which  would  require  that  the  protocol  and  the 
consent  form  be  modified.  Dr.  Fisher  was  told  that  Dr.  Cusick  had 
been  notified  and  the  European  protocol  and  consent  will  be  modi- 
fied. Dr.  Fisher  appreciated  our  willingness  to  provide  him  with  a 
copy  of  the  justification  document  for  this  label  change.  Dr.  Fisher 
did  comment  about  the  potential  negative  publicity  that  could 
occur.  In  particular,  this  could  be  the  bullet  being  sought  by  the 
health  industry  in  the  U.K.  to  stop  the  European  prevention  trial. 
If  this  is  the  case,  that  would  have  a  major  effect  in  the  United 
States.  He  agreed  that  we  should  be  prepared  for  this  potential 
negative  outcome." 

Now,  Dr.  Broder,  are  you  aware  of  this  exchange  between  Zeneca 
Pharmaceuticals  and  Dr.  Fisher  or  the  fact  that  the  people  in  these 
studies  were  concerned  about  how  the  B-14  trial  would  effect  the 
prevention  trial? 

Mr.  Broder.  I  was  not  aware. 

Mr.  DiNGELL.  Beg  your  pardon? 

Mr.  Broder.  I  am  not  aware. 

Mr.  DiNGELL.  What  do  you  make  of  this  memo?  It's  something 
that  should  have  been  brought  to  your  attention  or  to  the  attention 
of  the  NCI,  should  it  not? 

Mr.  Broder.  I  agree.  I  would  need  to  consult  with  Dr.  Ford.  May 
I  just  take  this  document  to  Dr.  Ford? 

Mr.  DiNGELL.  Sure.  Without  objection,  these  documents  relative 
to  Zeneca  Pharmaceuticals  will  be  inserted  in  the  record  at  the  ap- 
propriate place.  [See  p.  214.] 

Go  ahead,  Doctor. 

Mr.  Broder.  I'm  quite  disturbed  by  some  of  the  things  that  you 
just  read. 

Mr.  DiNGELL.  I  think  it  would  be  unfair  for  me  to  try  to  compel 
you  to  comment,  but  it  is  a  document  which  I  think  should  concern 
us.  Is  it  not?  It  tends  to  indicate  that  perhaps  maybe  the  pharma- 
ceutical house  and  Dr.  Fisher  have  not  been  sufficiently  forthcom- 
ing, though,  does  it  not? 

Mr.  Broder.  I'm  comparatively  concerned  that  I  don't  disagree 
with  what  you  have  just  said. 

Mr.  DiNGELL.  Now,  let's  look  at  this  situation.  Here  we've  got  the 
University  of  Pittsburgh.  Now,  the  University  of  Pittsburgh  solic- 
ited a  million  dollars  from  Zeneca  for  the  endowment  of  a  chair. 
They  wound  up  getting  $600,000.  This  is  while  the  test  of  this  par- 
ticular pharmaceutical  is  going  on. 

Does  that  seem  to  be  quite  cricket?  Dr.  Varmus,  do  you  want  to 
comment? 

Mr.  Varmus.  I  personally  have  concern  about  engaging  in  that 
kind  of  relationship. 

Mr.  DiNGELL.  I  wonder.  Does  it  pass  the  Aunt  Minnie  Sniff  Test? 

Mr.  Varmus.  What  test?  I'm  sorry. 

Mr.  DiNGELL.  If  Aunt  Minnie  were  to  sniff  this,  what  would  she 
say? 

Mr.  Varmus.  Can  you  explain  the  test  to  me,  sir? 

Mr.  DiNGELL.  Well,  Aunt  Minnie  is  somebody  we  use  around  here 
because  she  has  a  sensitive  nose.  What  we're  trying  to  figure  out 
is  would  she  like  the  smell  of  this  or  not. 


76 

Mr.  Varmus.  Probably  not. 

Mr.  DiNGELL.  Here  we've  got  the  University  of  Pittsburgh.  Let's 
go  through  some  of  the  times  that  we've  cut  their  track,  just  see. 
We  had  Dr.  Steven  Bruening.  He  pled  guilty  to  false  statements  in 
connection  with  the  making  of  a  number  of  tests  with  regard  to 
youngsters,  hyperactive  youngsters  and  mentally-impaired  young- 
sters, and  he  said  that  medication  should  not  be  given  them  to  sup- 
press the  activity.  He  did  this  on  the  basis  of  studies  which  he  said 
he  had  made,  which,  in  fact,  he  did  not  make. 

Then  we  had  a  fellow  by  the  name  of  Dr.  Herbert  Needleman. 
He  studied  the  exposure  of  children  to  lead.  Now,  this  was  re- 
viewed by  the  reviewing  authorities  and  they  said  that  the  reports 
were  false,  but  they  said  that  there  was  no  misconduct. 

Then  we  had  a  fellow  by  the  name  of  Dr.  Charles  Bluestone.  He 
took  large  sums  of  money  from  a  company  that  was  selling  drugs 
that  he  was  studying.  I  wonder  if  we  ought  not  get  the  University 
of  Pittsburgh  in  here  to  talk  to  us  about  these  matters. 

Mr.  Varmus.  I  have  inquired  myself  of  the  University  of  Pitts- 
burgh about  these  matters,  sir. 

Mr.  Broder.  We  have  received  correspondence  from  them  on 
these  points. 

Mr.  DiNGELL.  What  do  you  have  to  comment  either  with  regard 
to  the  correspondence  or 

Mr.  Varmus.  I  first  learned  from  a  letter  addressed  to  the  Sec- 
retary from  Senator  Rockefeller  and  Mr.  Waxman,  I  believe,  that 
there  was  a  report  in  Who's  Who  that  included  Dr.  Fisher's  entry 
claiming  that  he  occupied  the  ICI  professorship. 

I  asked  Dr.  Chabner,  who  was  then  in  Pittsburgh,  to  obtain  for 
me  some  information  about  this  relationship,  which  seemed  to  me 
not  to  pass  my  own  sniff  test.  What  we  learned  was  that  the  chair 
had  been  partly  endowed  by  the  ICI  and  that  Dr.  Fisher  had  not 
occupied  that  chair.  Now,  we  looked  ourselves  in  American  Men 
and  Women  of  Science  and  found  an  entry  that  included  that  pro- 
fessorship under  his  name. 

I  further  inquired  of  the  university  about  what  seemed  to  be  dis- 
crepancies in  these  accounts  and  I  was  told  that  was  a  clerical 
error  and  that  a  secretary  had,  to  Dr.  Fisher's  regret,  included  this 
in  his  biographical  listing,  that  it  was  not  accurate. 

I,  myself,  think  that  it  is  difficult  to  maintain  the  appearance  of 
propriety  and  possibly  the  practice  of  propriety  if  one's  own  depart- 
ment is  receiving  a  large  endowment  for  a  professorship  from  a 
company  that's  supplying  a  drug  that's  being  used  in  a  clinical 
study  being  carried  out  by  that  investigator. 

Universities  are  under  financial  stress,  but  the  issue  of  the  credi- 
bility of  research  that  results  from  university  activities  is  a  greater 
issue,  in  my  own  mind. 

Mr.  DiNGELL.  I  gather  Dr.  Fisher  is  still  being  compensated  by 
the  university. 

Mr.  Varmus.  Yes,  he  is. 

Mr.  DiNGELL.  So  whether  he  occupies  the  chair  is  really  of  lim- 
ited importance.  The  question  here  is  the  money,  not  who  occupies 
the  chair.  Somebody  else  is  occupying  the  chair,  but  chairs  seem  to 
be  somewhat  fungible.  In  other  words,  one  fellow  can  sit  in  them 


77 

or  another  fellow  can  sit  in  them.  It  doesn't  really  make  too  much 
difference  as  long  as  somebody  plays  the  chair. 

Mr.  Varmus.  I'm  just  providing  you  with  the  answers  I  received. 

Mr.  DiNGELL.  Did  you  say  nobody  occupies  the  chair? 

Mr.  Varmus.  Apparently,  the  amount  of  money  is  insufficient  to 
generate  the  income  that  would  be  required  to  pay  a  full  salary. 
Now,  at  some  institutions,  I  know  that  a  chair  may  not  pay  the  full 
salary,  but  still  constitute  a  chair.  It's  a  matter  of  definition. 

Mr.  DiNGELL.  I  have  seen  nothing  that  would  indicate  on  my  part 
any  concern  about  the  university  being  distressed  about  this  situa- 
tion. They  still  got  the  money,  right? 

Mr.  Varmus.  Yes. 

Mr.  DiNGELL.  We  have,  then,  a  question  about  the  status  of  the 
University  of  Pittsburgh's  assurances.  What  is  the  status  of  the 
University  of  Pittsburgh's  assurances  that  the — at  your  operation, 
if  you  please? 

Mr.  Chabner.  I'm  sorry,  sir.  I  don't  understand  the  question. 

Mr.  DiNGELL.  The  question  was  for  Dr.  Bivens.  But,  again,  we 
are  blessed  with  our  inadequate 

Mr.  BrvENS.  An  important  part  of  OKI's  work  is  to  review  the 
policies  and  procedures  that  are  used  by  institutions,  what  policies 
and  procedures  are  in  place  to  satisfy  the  regulatory  requirement 
for  an  assurance,  and  to  see  if  the  institution  is  following  its  own 
policies  and  procedures. 

We  do  have  a  major  compliance  review  underway  right  now,  re- 
viewing University  of  Pittsburgh  and  its  compliance  with  the  PHS 
regulations.  We  are  first  looking  at  their  existing  policies  and  pro- 
cedures to  see  if  they  comport  with  the  requirements  of  the  regula- 
tion and  then  we  are  looking  at  the  historical  record  of  how  they 
have  handled  inquiries  and  investigations  to  see  if  they  fit  with 
their  own  policies  and  procedures. 

If  we  identify  any  problems,  we  will  require  immediate  corrective 
action. 

Mr.  DiNGELL.  The  assurance  that  we're  referring  to  is,  of  course, 
the  assurance  of  scientific  integrity,  isn't  that  right? 

Mr.  BrvENS.  That's  correct,  sir. 

Mr.  DiNGELL.  What  happened  between  ORI  and  the  University 
of  Pittsburgh  regarding  this  assurance? 

Mr.  Bivens.  I  don't  recall  in  my  tenure  any  specific  interchange 
between  ORI  and  Pittsburgh  related  to  their  assurance. 

Mr.  DiNGELL.  Should  you  consider  suspending  this  and  didn't,  in 
fact,  you  consider  suspending  the  scientific  integrity  assurance 
pending  improved  performance  by  the  university? 

Mr.  Bivens.  Not  while  I  was  Director.  I  became  Director  in  Janu- 
ary 1993.  There  mav  have  been  a  prior  history  with  the  old  offices, 
OSI  and  OSIR,  and  even  my  old  office,  OSIR,  I  don't  recall  that 
kind  of  interchange.  But  we  certainly  have  that  option  of  suspend- 
ing the  assurance. 

Mr.  DiNGELL.  Clearly,  your  predecessor  had  that  option  because 
these  events  occurred  apparently  just  previous  to  the  time  that  you 
assumed  your  current  responsibilities. 

Can  you  tell  us  what  the  records  of  your  agency  show? 

Mr.  Bivens.  I  would  have  to  look  at  those.  I'm  not  familiar  with 
them  right  now. 


78 

Mr.  DiNGELL.  Would  you  do  that  and  make  that  information 
available  to  the  committee,  please? 

Mr.  BlVENS.  I'd  be  glad  to. 

Mr.  DiNGELL.  The  Chair  is  going  to  recognize  the  gentlewoman 
from  Pennsylvania. 

Ms.  Margolies-Mezvinsky.  Thank  you,  Mr.  Chairman.  Dr. 
Broder,  for  the  sake  of  fairness,  it's  important  to  emphasize,  I 
think,  that  Dr.  Fisher  has  not  only  not  been  found  guilty  of  sci- 
entific misconduct,  he's  not  even  under  investigation.  Is  that  cor- 
rect? 

Mr.  Broder.  That  is  absolutely  correct. 

Ms.  Margolies-Mezvinsky.  You  have  removed  him  as  a  prin- 
cipal investigator,  as  administrator  of  the  NSABP  program.  We 
have  been  told  that  he  was  removed  because  NCI  had  some  doubt 
about  his  continued  fitness  to  serve  as  principal  investigator.  We've 
gotten  some  calls  in  our  office  from  some  of  his  patients  who  say 
that  he  was  a  really  fine  physician,  saved  their  lives,  all  those 
things. 

Can  you  describe  for  the  subcommittee  the  principal  of  fitness 
and  how  you  applied  it  in  his  case? 

Mr.  Broder.  Thank  you  for  the  question.  The  word  "fitness",  if 
that's  the  right  calculus  that  we  would  use  here,  does  not  go  to 

Ms.  Margolies-Mezvinsky.  What  word  would  you  use? 

Mr.  Broder.  I  would  use  suitability.  But  I  didn't  do  a  legal  anal- 
ysis and  I  don't  think  we  did  the  kind  of  exact  word.  But,  basically, 
the  bottom  line  is  that  what  we  felt  was  that  Dr.  Fisher  could  not 
be  the  individual  with  whom  we  corresponded  on  matters  of  the 
performance  of  this  grant,  which  had  to  ao  with  things  such  as  spe- 
cific compliance  with  our  rules,  specific  implementation  of  auditing 
procedures,  proper  notification  of  problems,  all  the  things  that  we 
have  talked  about  and  many  of  the  issues  that  I  raised  in  my  open- 
ing statement. 

This  was  not  a  determination  and  should  not  be  construed  as  a 
determination  that  Dr.  Fisher  is  not  fit  to  function  as  a  surgeon  or 
as  a  clinical  scientist.  That  is  not  what  we  are  saying  and  that  is 
not  what  we  are  talking  about  today.  That  is  why  I  tried  in  my 
opening  statement  to  draw  a  distinction  between  his  formidable  in- 
tellect and  formidable  record  in  spite  of  all  the  things  that  we 
talked  about,  his  contributions.  Dr.  Fisher  is  a  Lasker  Award  win- 
ner. He  has  made  a  number  of  contributions. 

My  position  is  none  of  that  matters  in  our  analysis  of  who  shall 
run  a  grant  that  we  administer.  It  has  to  do  with  the  performance 
of  the  individual  here  and  now. 

Ms.  Margolies-Mezvinsky.  Dr.  Varmus? 

Mr.  Varmus.  Yes.  I  agree  with  that  statement. 

Ms.  Margolies-Mezvinsky.  And  you  support  the  NCI's  action  re- 
garding Dr.  Fisher. 

Mr.  Varmus.  The  NCI  recommended  to  the  university  that  Dr. 
Fisher  be  replaced  as  the  director  of  that  project  for  administrative 
cause,  and  I  agree  with  that  assessment. 

Ms.  Margolies-Mezvinsky.  How  do  you  view  this  standard  of, 
whatever  you  want  to  call  it,  fitness,  suitability,  and  how  do  you 
believe  it  should  be  applied  in  other  cases? 

Mr.  Broder.  To  whom  is  the  question? 


79 

Ms.  Margolies-Mezvinsky.  Dr.  Varmus. 

Mr.  Varmus.  This  is  a  case-by-case  analysis.  It's  an  unusual  cir- 
cumstance, but  we  had  a  very  significant  problem  on  our  hands, 
which  is  the  focus  of  this  hearing  today;  namely,  that  the  precipi- 
tating feature  here  was  the  failure  of  the  NSABP  to  publicly  dis- 
tribute the  results  of  the  ORI  investigation  and  the  reanalysis  of 
the  NSABP  study,  known  as  B-06.  Under  those  circumstances,  it 
was  proper  that  the  NCI  evaluate  administrative  practices  at  the 
NSABP  and  what  they  found  were  a  number  of  failures  of  adminis- 
trative oversight  that,  to  my  mind,  called  for  Dr.  Fisher's  replace- 
ment. 

Now,  in  similar  circumstances,  I  would  advise  the  same  thing. 
This  is  an  unusual  occasion  in  the  history  of  clinical  research  in 
this  country.  At  the  moment,  I  don't  see  any  clear  simple  prescrip- 
tion for  the  conditions  under  which  similar  actions  would  be  ad- 
vised. 

Ms.  Margolies-Mezvinsky.  We  are  talking  about  the  application 
of  a  principal,  correct? 

Mr.  Varmus.  Yes. 

Ms.  Margolies-Mezvinsky.  Are  we  applying  the  application  of 
this  principal  consistently? 

Mr.  Varmus.  We  are,  but  we  don't  have  very  many  cases  to  apply 
it  to  at  this  point. 

Ms.  Margolies-Mezvinsky.  Dr.  Broder,  does  the  principal  of  fit- 
ness or  suitability  also  apply  to  intramural  NCI  scientists? 

Mr.  Broder.  It  most  certainly  does. 

Ms.  Margolies-Mezvinsky.  What  about  Dr.  Gallo? 

Mr.  Broder.  Is  there  a  specific  question  about  Dr.  Gallo  or  do 
you  wish  me  just  to  make  a  general  comment? 

Ms.  Margolies-Mezvinsky.  Is  it  still  under  consideration  or  are 
you  applying  that  principal? 

Mr.  Broder.  Dr.  Varmus  and  I  have  discussed  a  number  of  is- 
sues related  to  Dr.  Gallo.  The  issues  involving  Dr.  Gallo  have  until 
recently  been  complicated  by  a  formal  inquiry  process  that  has 
gone  from  OSI  to  ORI.  We  were  awaiting  the  results  of  that  process 
to  end  and  also  to  have  the  kind  of  factfinding  that  we  needed  to 
do  in  order  to  make  a  decision. 

In  Dr.  Fisher's  case,  we  believed  that  there  was  sufficient  and 
compelling  facts  at  our  disposal,  specific  facts  that  related  to  his 
specific  performance  in  a  specific  way,  including,  among  all  the 
other  things,  our  detection  of  a  report  of  yet  an  additional  site  in 
Canada  which  subsequently  turned  out  to  be  an  indicia  of  serious 
data  manipulation  in  another  patient,  which  Dr.  Fisher  had  still, 
after  all  of  our  warnings,  still  not  reported  to  us. 

So  we  believed  that  the  facts  in  that  case  could  allow  but  only 
one  conclusion  in  this  specific  situation.  But  we  will  review  the  sit- 
uation and  the  facts  of  Dr.  Gallo's  case.  Staff  members  have  been 
very  kind  in  providing  information  to  me  and  I  believe  will  be 
meeting  with  me  again. 

Ms.  Margolies-Mezvinsky.  I  don't  think  we're  trying  to  get  into 
the  personnel  action.  I  think  we're  trying  to  get  into  the  principal, 
if  you're  going  to  apply  the  same  principal. 

Mr.  Broder.  The  answer  is  yes.  We  will  apply  it  to  all  grantees 
and  to  the  intramural  program.  But  the  jobs  may  be  different. 


80 

There  may  be  different  aspects  of  what  you  apply  to  each  different 
employee.  Dr.  Fisher  has  the  right  to  assert  to  us  that  he's  a  very 
good  surgeon  and  a  very  good  clinical  researcher  and  were  we  deal- 
ing with  a  grant  that  uniquely  was  funding  him  as  a  surgeon  or 
as  a  clinical  researcher  or  as  someone  who  took  care  of  patients, 
as  you  may  have  implied,  we  would  not  be  saying  we  have  concerns 
about  his  capacity  to  provide  excellent  state-of-the-art  care  to  a  pa- 
tient. That  is  not  the  basis  of  his  removal  from  being  a  principal 
investigator. 

Ms.  Margolies-Mezvinsky.  Do  you  believe  that  the  principal  of 
fitness,  suitability  or  whatever  you  want  to  call  it  should  apply  to 
all  NIH  intramural  scientists? 

Mr.  Varmus.  Yes,  I  do. 

Ms.  Margolies-Mezvinsky.  Dr.  Broder,  isn't  it  true  that  NCI 
has  always  possessed  the  authority  and  the  ability  to  apply  these 
standards  and  to  take  the  actions  that  you  have  taken  in  this  case? 

Mr.  Broder.  Yes. 

Ms.  Margolies-Mezvinsky.  Have  these  standards  and  actions 
previously  been  routinely  applied  or  are  we  seeing  something  new? 

Dr.  Broder.  I  am  not  aware  of — I  personally  am  not  aware,  and 
staff  will  have  to  inform  me.  I  am  not  aware  of  the  NCI  asserting 
its  rights  under  the  Code  of  Federal  Regulation  and  other  applica- 
ble statutes  to  demand  data  from  an  investigator,  disseminate  that 
date,  publish  the  data  without  the  investigator's  necessary  involve- 
ment even,  possibly  even  against  the  will  of  the  investigator.  I  am 
not  aware  of  that  principal  ever  having  been  implemented.  But  it 
has  been  now  and  we  will  not  hesitate  to  do  it  again  if  a  fraud 
issue  comes  up. 

It  has  a  downside,  however,  in  that  it  could  create  situations  in 
which  we  at  NCI  are  making  statements  which  are  at  variance 
from  a  formidable  intellect  and  leader  in  a  field,  and  that  also  has 
its  downsides.  That's  why  our  hope  had  been — this  is  an  expla- 
nation, not  an  excuse. 

Our  hope  had  been  that  we  could  reach  a  situation  where  Dr. 
Fisher,  with  our  assistance,  would  take  the  lead  to  first  come  for- 
ward with  all  the  different  issues. 

Ms.  Margolies-Mezvinsky.  Dr.  Varmus,  do  you  support  NCI's 
willingness  to  exercise  this  existing  authority  and  will  we  see  simi- 
lar actions,  if  necessary,  across  the  board  at  NIH? 

Mr.  Varmus.  I  support  it  in  this  case  and,  by  implication,  I 
would  support  it  in  other  situations  that  are  comparable. 

Ms.  Margolies-Mezvinsky.  Thank  you.  I  yield  the  balance  of  my 
time,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  recognizes  the  gentleman  from  Ohio. 

Mr.  Brown.  Thank  you,  Mr.  Chairman.  Dr.  Broder,  on  the  sub- 
ject of  willingness  to  deal  forthrightly  with  scientific  fraud  in,  I  be- 
lieve, July  of  1991,  you  were  briefed  by  OSI  concerning  its  findings 
of  falsification  and  its  findings  of  fabrication  of  St.  Luc  data. 

Describe,  if  you  would,  what  you  were  told,  what  directives  you 
issued  pursuant  to  that  briefing. 

Mr.  Broder.  Yes.  I  believe  the  committee  has  a  memo  for  the 
record  prepared  by  Dr.  McFarland  in  this  regard.  I  received  a  sum- 
mary from  individuals  with  firsthand  knowledge  of  the  fraud  at  Le 
Hopital  St.  Luc  in  Montreal.  It  was  very  clear  to  me  that  there  was 


81 

a  serious  problem  of  overt  fraud  and  that  the  issue  had  to  be  dealt 
with  forthrightly  and  effectively. 

We  determined  that  we  would  cooperate  with  ORI  and  provide 
whatever  resources  we  could.  I  determined  at  that  time  that  the 
only  course  of  action  that  could  be  taken  would  be  to  segregate  the 
data  from  the  Le  Hopital  St.  Luc  and  permanently  pull  it  out  of 
future  analyses,  but  providing  the  data — providing  analyses  both 
with  and  without  the  data,  but  permanently  notifying  individuals 
that  the  data  had  to  be  pulled  out,  and,  also,  taking  steps  to  appro- 
priately reanalyze  and  republish  the  data  with  the  appropriate 
interactions  with  the  Office  of  ORI,  although  it  may  not  have  been 
called  ORI  in  that  era. 

It  was  at  that  point  the  predecessor  organization  for  ORI. 

Mr.  Brown.  So  I  take  it  NCI  and  Pittsburgh  simply  didn't  follow 
your  direction. 

Mr.  Broder.  Speaking  as  to  the  effects  of  the  University  of  Pitts- 
burgh, they  certainly  did  not  follow  our  very  constructive  criti- 
cisms. As  to  NCI  staff,  I  will  accept  responsibility  for  this  issue. 

Mr.  Brown.  This  seems  to  be  the  picture.  We  have  the  Director 
of  NCI  telling  subordinates  to  have  University  of  Pittsburgh  reana- 
lyze the  data,  republish  the  analysis,  not  publish  further  studies 
using  this  falsified  fabricated  data;  yet,  every  single  directive  was 
disobeyed,  ignored,  taken  too  lightly,  whatever.  Why?  What  hap- 
pened? 

Mr.  Broder.  I  believe  it  is,  in  part,  a  function  of  Dr.  Fisher's  for- 
midable reputation  and  I  believe  that  the  staff  were  attempting  to 
negotiate  a  collegial  non-confrontation  way  of  dealing  with  a  pio- 
neering figure  who  obviously  knew  a  great  deal.  I  believe  there  was 
an  excessive  level  of  collegiality  and  a  higher  level  of  tolerance 
than  is  now  the  case.  That  is  probably  the  best  way  that  I  can  sum- 
marize this. 

Staff  simply  did  not  wish  to  confront  and  order  Dr.  Fisher,  who, 
after  all,  is  the  person  that  had  made  many  contributions,  had  a 
great  deal  of  status  in  the  scientific  community.  I  believe  that  is, 
in  part,  responsible  for  what  happened. 

The  other  issue,  which  is  of  no  comfort  to  the  committee  or  the 
public,  but  which  is,  I  think,  one  of  the  factors  that  should  be  put 
on  the  table,  is  that  the  staff  felt  that  Dr.  Fisher  had  been  right 
on  a  number  of  occasions  that,  in  fact,  there  were  no  changes  that 
would  come  from  this  and  that  other  studies  already  available  were 
confirming  the  value  of  breast-sparing  surgery.  So  all  of  those  fac- 
tors came  into  the  mix. 

I  do  believe  that  had  there  been  a  public  health  hazard,  that  the 
other  steps  would  have  been  taken,  but  that's  of  no  consolation  to 
the  committee  and  I  accept  your  point. 

Mr.  Brown.  Dr.  Varmus,  according  to  Dr.  Broder,  it  sounds  a  lit- 
tle bit  like  Congress,  collegiality,  protecting  people,  people  protect- 
ing themselves,  all  of  that.  It  sounds  like  the  criticisms  that  people, 
sometimes  rightly,  level  at  this  institution. 

What  is  the  rationale  beyond  that  for  why  Dr.  Fisher  and  his  col- 
leagues would  continue  to  submit  and  publish  papers  that  are 
known  to  contain  that  false  data?  What,  building  on  what  Dr. 
Broder  said,  is  that  rationale  for  Dr.  Fisher  to  do  that? 


82 

Mr.  Varmus.  I  think  these  are  questions  that  should  be  ad- 
dressed to  Dr.  Fisher.  But  I  think  there  are  some  potential  expla- 
nations that  have  to  do  with  the  desire  to  publish  the  findings  of 
studies  that  have  been  carried  out  in  multiple-institutions. 

I  cannot  myself  condone  the  inclusion  of  data  from  the  St.  Luc 
Hospital  once  fraud  at  St.  Luc's  had  been  ascertained.  To  my  way 
of  thinking,  information  from  that  hospital  should  have  been  ex- 
cluded from  any  further  publication.  So  I  don't  want  to  pretend  to 
understand  how  that  came  to  be.  I  think  you  really  need  to  address 
those  questions  to  Dr.  Fisher  and  other  members  of  the  NSABP. 

Mr.  Brown.  Let  me  ask  it  a  different  way.  Let  me  ask  Dr.  Broder 
in  this  case.  The  subcommittee  staff  has  found  that  as  early  as 
July  of  1992  that  NCI  officials  were  admonishing  Dr.  Fisher,  ad- 
monishing his  colleagues  to  upgrade  and  strengthen  auditing  proce- 
dures. What  was  the  response  of  Dr.  Fisher  and  what  was  the  re- 
sponse of  his  colleagues  to  those  repeated  requests  from  NCI? 

Mr.  Broder.  I  would  say  that  Dr.  Fisher's  response  to  us  was 
quite  disrespectful  of  the  role  that  government  employees  play  and 
quite  disrespectful  of  the  status  and  functions  that  we  have  and, 
I  think  I'm  accurately  paraphrasing,  basically  said  words  to  the  ef- 
fect of  who  are  you  to  criticize  me,  I  know  how  to  do  clinical  trials, 
I've  been  doing  them  before  you  were  a  doctor. 

That's  not  literally  what  he  said,  but  I  am  giving  you  my  edi- 
torial response.  I  believe  our  staff  referred  to  some  of  his  things 
and  tried  to  give  him  constructive  criticism,  which  he  rejected  out 
of  hand. 

Mr.  Brown.  So  what's  the  next  step?  What  was  the  next  step? 
If  he  responded  to  you  that  arrogantly  and  with  that  haughtiness, 
if  you  will,  and  with  that  self-certitude  or  self-righteousness,  what 
was  your  response  back? 

Mr.  Broder.  I  believe  the  staff  continued  the  process  of  negotiat- 
ing with  him  and  bending  him  to  the  things  that  needed  to  be 
done.  They  did,  in  fact,  negotiate  successfully  for  him  to  accept  cer- 
tain changes,  at  least  as  we  were  informed  about  them.  We  made 
our  point  with  respect  to  the  institution  of  data  safety  monitoring 
boards  and  other  things  that  he  was  instructed  to  do. 

They  had  been  given  assurances  that  papers  were  being  prepared 
and  that  reanalyses  were  coming,  and  I  think  that  that — it  was  a 
slow  process,  but  I  believe,  speaking  for  the  staff,  they  thought 
they  were  moving  in  the  right  direction  and  that  they  were  pre- 
serving Dr.  Fisher  as  a  force  who  could  contribute  and  continue  to 
do  good  in  a  method  that  was  collegial. 

Mr.  Brown.  We  have  seen  a  number  of  reports  of  NSABP  audits 
that  reflect  significant  discrepancies  in  the  audited  records  of  var- 
ious research  sites.  What  are  NSABP's  duties  and  responsibilities 
regarding  audit  follow-ups  and  recommendations? 

Mr.  Friedman.  Currently,  under  the  new  branch  which  has  been 
just  identified  and  even  prior  to  the  establishment  of  that  branch, 
the  NSABP  is  having  a  complete  overhaul  of  how  their  on-site  au- 
diting is  conducted.  If  you're  interested,  I  can  describe  the  inad- 
equacies of  the  previous  program  or  I  can  simply  give  you  informa- 
tion about  the  current  program. 

Mr.  Brown.  Do  both,  please. 


83 

Mr.  Friedman.  All  right,  sir.  In  the  past,  rather  than  having  an 
audit  where  investigators  would  go  to  the  site  that  the  research  is 
being  conducted  and  to  examine  records  from  that  site  and  look  for 
supporting  information,  the  way  the  NSABP  conducted  their  audits 
was  to  have  individusds  go  xerox  records  and  bring  them  back  to 
Pittsburgh.  In  addition,  whereas  our  other  cooperative  groups — and 
this  is  a  very  important  point,  sir. 

In  contrast  to  how  our  other  cooperative  groups  operate,  the 
number  of  charts  sampled  at  each  of  these  research  sites  was  rel- 
atively small.  Instead  of  having  a  larger  number  of  charts  sampled 
from  a  larger  enrolling  institution,  they  had  a  small  fixed  number 
of  charts  examined  at  each  institution. 

This  was  not — although  it  was  defended  by  the  NSABP,  this  was 
not  a  system  that  we  felt  was  entirely  appropriate  or  would  be  as 
efficient  as  we  would  like.  We  were  very  concerned  about  the  dis- 
covery of  the  fraud  at  St.  Luc  Hospital  and  wanted  very  much  to 
try  and  look  carefully  at  their  system  and  bring  it  at  least  up  to 
the  standards  of  other  cooperative  groups. 

Currently,  the  monitoring  program  for  the  NSABP  is  to  have  a 
larger  number  of  charts  sampled,  to  have  researchers  go  to  those 
individual  sites  and  actually  look  at  the  primary  data,  an  x-ray  or 
an  EKG  form  or  whatever  is  at  that  site,  to  confirm  the  reliability 
and  truthfulness  of  that. 

We  have  been  very  concerned  about  the  whole  credibility  of  the 
lumpectomy  trial  because,  as  was  expressed  this  morning,  there  is 
so  much  public  concern  about  it  and  it  would  be  wrong  for  us  to 
not  be  attentive  to  that  concern.  We  have  been  very  careful  to  go 
and  look  at  more  than  850  research  records,  the  primary  patient 
charts  of  patients  who  enrolled  in  the  B-06 — that  is  the 
lumpectomy  trial — to  examine  those  records  to  see  if  there's  any 
systematic  fraud  or  falsification. 

We  also  examined  a  number  of  other  charts,  all  together  almost 
1,400  charts,  looking  at  many  different  studies,  to  try  and  confirm 
that,  in  fact,  despite  the  unsatisfactory  nature  of  the  system  that 
existed  previously,  that  we  could  still  have  confidence  in  the  con- 
clusions that  these  investigators  were  describing. 

Mr.  Brown.  Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman.  The  gentleman 
from  Colorado. 

Mr.  SCHAEFER.  Thank  you,  Mr.  Chairman.  Just  a  few  wind-up 
questions.  Dr.  Varmus,  I  understand  that  approximately  a  million 
dollars  of  the  taxpayers'  money  was  used  in  the  St.  Luc  research. 
Are  there  any  efforts  underway  to  determine  whether  this  money 
can  be  reclaimed? 

Mr.  Varmus.  Yes,  there  are.  We've  been  trying  to  reclaim  the 
money.  As  you  understand,  there  are  jurisdictional  problems,  with 
the  St.  Luc  Hospital  being  located  in  Montreal,  and  we've  asked  the 
Department  of  Justice  for  help  in  trying  to  recover  the  funds. 

Mr.  SCHAEFER.  Does  the  University  of  Pittsburgh — after  you. 

Mr.  DiNGELL.  Would  you  give  us  a  report  on  the  status  of  mat- 
ters with  regard  to  the  assistance  of  the  Department  of  Justice, 
please? 

Mr.  Varmus.  For  the  record,  yes. 


84 

Mr.  DiNGELL.  Not  right  at  this  minute,  but  just  when  it's  com- 
fortable. 

Mr.  Varmus.  Absolutely. 

Mr.  SCHAEFER.  May  the  University  of  Pittsburgh  have  any  liabil- 
ity in  this? 

Mr.  Varmus.  They  might.  We're  looking  into  that  as  well. 

Mr.  SCHAEFER.  That's  all  part  of  it.  And  this  is  what  we're  going 
to  get  an  update  on. 

Mr.  Varmus.  We  can  provide  you  with  a  detailed  account  of  that 
from  our  general  counsel. 

Mr.  ScHAEFER.  Can  you  tell  me  if  these  efforts  to  retrieve  the 
money  were  begun  before  or  after  the  subcommittee  started  looking 
at  this? 

Mr.  Varmus.  As  far  as  I  know,  after. 

Mr.  SCHAEFER.  After. 

Mr.  Varmus.  After  I  was  informed  of  some  of  these  concerns. 

Mr.  SCHAEFER.  Right. 

Mr.  Varmus.  As  you  know,  I'm  new  at  NIH,  but  when  I  heard 
about  them,  we  began  to  look  into  this  question. 

Mr.  SCHAEFER.  So  once  our  subcommittee  began  looking  into  this 
matter,  then  steps  were  taken  to  try  to  reclaim  it. 

Mr.  Varmus.  That's  correct. 

Mr.  SCHAEFER.  I  thank  the  subcommittee  for  that.  It's  a  million 
dollars.  Are  you  looking  in  your  files  to  see  if  there's  attempts 
being  made  to  recover  taxpayers'  dollars  in  other  instances  where 
fraud  was  involved? 

Mr.  Broder.  Sir,  we  are.  We  consider  that  we — we  have  a  man- 
ual that  has  been  implemented  in  which  fraud  will  always  be  pre- 
sumed, a  rebuttable  presumption,  but  will  always  be  presumed  to 
indicate  recovery.  Then  we  will  act  against  the  grantee  according 
to  the  advice  that  we  receive  from  the  Office  of  General  Counsel 
and  according  to  applicable  principals  of  law  and  Federal  regula- 
tions. 

This  will  be  automatic  and  it  is  clearly  understood  in  our  grants 
management  process  and  so  on. 

Mr.  SCHAEFER.  Had  this  been  done  before  this  situation,  before 
our  subcommittee  started 

Mr.  Varmus.  I've  been  informed  by  Dr.  Baldwin  it's  been  done 
twice  before. 

Mr.  SCHAEFER.  OK.  Mr.  Chairman,  I'm  finished. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman.  Dr.  Bivens,  what 
other  cases  presently  active  at  ORI  or  other  during  your  tenure 
that  have  been  closed  with  a  finding  of  misconduct  involved  clinical 
trials  or  impact  upon  the  public  health? 

Mr.  Bivens.  I  believe  that  the  St.  Luc  case  is  the  only  one  in 
which  there  was  a  confirmed  scientific  misconduct  finding  related 
to  a  clinical  trial. 


85 

Mr.  DiNGELL.  Which  one  would  that  be?  Can  you  tell  us  about 
presently  active  ones? 

Mr.  BiVENS.  Presently  active  ones? 

Mr.  DiNGELL.  Yes,  sir. 

Mr.  BrvENS.  My  understanding  is  that  there  is  an  investigation 
underway  and  an  inquiry  underway  on  two  trials  funded  by  the 
National  Eye  Institute. 

Mr.  DiNGELL.  National  Art  Institute? 

Mr.  BlVENS.  Eye  Institute.  I'll  be  glad  to  provide  more  informa- 
tion on  those.  I  don't  have  it  ready  at  hand  at  the  moment. 

Mr.  DiNGELL.  If  you  please. 

[The  following  information  was  received:] 


86 


REPORT  ON  ACTIVE  ORI  CASES  INVOLVIKG  MXILTICENTER  CLINICAL  TRIALS 

A.    Investigation  into  possible  falsification  and  fabrication  of 
data  in  the  PES  funded  COLLABORATIVE  OCULAR  MELANOMA  STUDY 
at  Northwestern  University  Medical  Center  (93-27)  and  The 
Cleveland  Clinic  Foiindation  (93-28) 

Funded  by  the  National  Eye  Institute  (HEX) ,  National  Institutes 
of  Health,  The  Collaborative  Ocular  Melanoma  Study  (COMS) 
consists  of  two  multicenter,  randomized  controlled  clinical 
trials  designed  to  investigate  the  efficacy  of  radiation  therapy 
compared  to  surgery  in  prolonging  the  vision  and  survival  of 
patients  presenting  with  choroidal  melanoma,  a  rare  intraocular 
cancer . 

Approximately  1500  new  cases  of  choroidal  melanoma  are  diagnosed 
each  year  within  the  U.S.   The  liver  is  the  most  frequent  site  of 
metastasis.   The  median  survival  after  diagnosis  of  metastatic 
disease  is  6-9  months;  therefore,  choroidal  melanoma  is  indeed 
life  threatening.   The  most  widely  used  treatment  for  choroidal 
melanoma  of  all  sizes  has  been  removal  of  the  eye  (e.g., 
enucleation) .   Radiation  therapy  has  been  advocated  as  an 
alternative  treatment  with  the  goal  of  preserving  the  eye  and 
possibly  some  vision  in  the  affected  eye. 

Patients  presenting  with  unilateral  choroidal  melanoma  classified 
as  "medium"  in  size  are  randomized  with  equal  probability  to 
either  enucleation  or  radiation  therapy  by  application  of  a 
radioactive  plaque  sutured  to  the  eye  over  the  base  of  the  tumor. 
Patients  with  large  tvimors  are  randomized  with  equal  probability 
to  either  enucleation  or  a  five  day  course  of  external  beam 
radiation  therapy  followed  by  enucleation.   (Controlled  Clinical 
Trials.  14:362-391,  1993). 

Clinical  data  on  COMS-eligible  patients  in  each  of  the  more  than 
4  0  participating  centers  is  forwarded  to  the  COMS  Coordinating 
Center  for  entry  into  the  study  database  and  statistical 
analyses.  The  Coordinating  Center  is  located  at  the  Wilmer 
Ophthalmological  Institute,  The  Johns  Hopkins  University, 
Baltimore,  MD,  and  is  supported  by  a  cooperative  agreement. 

No  results  of  the  COMS  clinical  trials  have  been  published  at 
this  time.   The  protocol  for  the  study  was  published  in  1993  and 
is  referenced  above . 

The  COMS  Coordinating  Center  identified  possible  falsification 
and  fabrication  of  records  submitted  from  two  of  the 
participating  COMS  centers,  the  Northwestern  University  Medical 
Center  and  The  Cleveland  Clinic  Foundation,  on  April  14,  1993, 
and  on  June  28,  1993,  respectively.   The  NEI  program  officer  was 
alerted  about  the  discrepancies  in  the  Northwestern  COMS  data  on 


87 


May  21,  1993.   Similar  discrepancies  in  data  from  the  Cleveland 
Clinic  Foundation  program  were  revealed  at  a  meeting  of  the  COMS 
Data  Safety  and  Monitoring  Committee  on  October  4,  1993. 

ORI  was  informed  of  the  data  reporting  discrepancies  at  the 
Northwestern  COMS  center  on  August  26,  1993,  by  a  telephone  call 
from  the  NET  misconduct  policy  officer.   ORI  was  informed  of  the 
data  reporting  discrepancies  associated  with  The  Cleveland  Clinic 
Foundation  COMS  center  on  October  5,  1993,  during  a  meeting 
between  NEI  and  ORI  staff  which  had  been  scheduled  to  discuss 
the  Northwestern  findings. 

The  Northwestern  University  Medical  Center; 

The  Northwestern  University  Medical  Center  has  been  a  participant 
in  the  COMS  program  since  198  6.  Until  recently,  the  Northwestern 
COMS  program  registered  the  largest  patient  enrollment  (103)  of 
all  the  participating  COMS  centers  nationwide  and  in  Canada.  In 
1992-1993,  Northwestern  University  received  $127,700  in  PHS 
support  for  its  participation  in  COMS. 

Identified  discrepancies  in  the  reporting  of  clinical  trial  data 
at  the  Northwestern  COMS  Center  were  brought  to  the  attention  of 
University  officials  and  to  the  COMS  Coordinating  Center  on  April 
14,  1993,  by  the  Principal  Investigator.   He  stated  that 
inaccurate  data  (e.g.,  misrepresentation  of  examination  dates  and 
other  dates  associated  with  laboratory  tests.  X-rays,  etc.)  were 
supplied  to  the  COMS  Coordinating  Center  by  the  Northwestern  COMS 
clinical  coordinator  who  was  immediately  placed  on  leave  from  the 
progreua;  employment  was  terminated  later  in  April  without  an 
official  University  inquiry.  The  COMS  Coordinating  Center 
dispatched  an  audit  team  to  the  Northwestern  COMS  center  on  April 
22  and  again  on  June  1,  1993.   A  University  committee  of  inquiry 
was  established  on  May  20,  1993,  to  examine  the  issue  of  possible 
scientific  misconduct  within  the  COMS  program  and  to  make  a 
recommendation  to  University  officials  regarding  the  need  for  a 
full  investigation.   The  inquiry  committee  submitted  its 
recommendation  that  an  investigation  was  warranted  in  a  report  to 
the  Vice  President  for  Research  and  Graduate  Studies  on  October 
5,  1993. 

The  Division  of  Research  Investigations  (DRI)  in  ORI  was  notified 
on  August  26,  1993,  by  the  NEI  of  data  reporting  discrepancies  at 
the  Northwestern  COMS  center  and  told  that  the  institution  was 
conducting  an  inquiry.   DRI  met  with  the  NEI  misconduct  officer 
to  obtain  additional  information  and  a  copy  of  the  COMS 
Coordinating  Center  audit  report,  and  informed  Northwestern 
University  officials  on  October  12,  1993,  of  its  intent  to  open  a 
case  and  to  conduct  a  direct  investigation.   The  DRI  requested 
the  University  to  cease  its  investigation  of  the  COMS  matter  and 
to  secure  all  COMS  patient  medical  and  research  files.   Based  on 
the  Coordinating  Center  audit  report  and  the  Northwestern  inquiry 
report,  DRI  identified  the  potential  respondents  in  the  case. 


88 


DRI  visited  Northwestern  University  on  February  7-11,  1994. 
Medical  and  research  files  of  all  103  eligible  patients  enrolled 
in  the  COMS  program  were  reviewed  against  data  submitted  to  the 
coordinating  center.   COMS  Coordinating  Center  staff  provided 
technical  support  during  the  review.   Several  key  witnesses  and 
all  but  one  of  the  possible  respondents  were  questioned  and  their 
testimony  recorded.   The  DRI  analyses  of  the  evidence  obtained  at 
the  site  visit  and  final  conclusions  remain  to  be  finalized  at 
this  time. 

There  were  a  number  of  data  items  reported  for  the  Northwestern 
patients  which  could  not  be  confirmed  because  documentation  was 
not  available.   These  issues  remain  to  be  resolved. 


The  Cleveland  Clinic  Foiuidation: 

The  Cleveland  Clinic  Foundation  has  been  a  participant  in  the 
COMS  program  since  198  6;  investigators  have  entered  24  patients 
on  the  study.   The  Cleveland  Clinic  Foundation  receives  funds 
through  a  subcontractual  agreement  with  the  COMS  Coordinating 
Center  at  the  Johns  Hopkins  University;  funds  allocated  to  The 
Cleveland  Clinic  Foundation  COMS  program  for  the  ninth  year 
(1993-1994)  of  the  study  total  $20,762. 

Identified  discrepancies  in  the  reporting  of  clinical  trial  data 
from  The  Cleveland  Clinic  Foundation  came  to  the  attention  of  the 
COMS  Coordinating  Center  through  a  routine  audit  of  patient  files 
by  a  representative  of  the  Coordinating  Center  on  June  28,  1993. 
The  initial  purpose  of  the  visit  by  the  Coordinating  Center 
representative  was  to  review  the  current  status  of  clinic 
operations  and  to  assist  in  resolving  any  problems  that  arose 
since  the  previous  clinic  visit  or  that  were  identified  during 
the  current  visit.  Identified  discrepancies  included: 

1)  blood  test  results  were  reported  as  normal  but  no 
record  was  available  to  confirm  the  test  was  performed; 

2)  falsification  of  dates  for  patient  examinations  so  as 
to  be  compatible  with  protocol  restrictions; 

3)  reporting  of  blood  test  results  as  normal  when  the 
results  were  abnormal; 

4)  a  COMS  certified  examiner  was  identified  as  having 
performed  an  evaluation  when  the  evaluation  was 
actually  performed  by  a  non-COMS  certified  staff 
member. 

Although  the  data  reporting  discrepancies  associated  with  The 
Cleveland  Clinic  Foundation  COMS  center  were  known  to  the  COMS 
Coordinating  Center  at  the  end  of  June  1993,  this  information  was 
not  brought  to  the  attention  of  the  NEI  until  the  October  4, 
1993,  meeting  of  the  COMS  Data  Safety  and  Monitoring  Committee. 


89 


The  NEI  Program  Officer  alerted  the  NEI  misconduct  policy 
officer,  on  October  4,  who,  in  turn,  alerted  the  ORI  on  October 
5,  1993. 

On  October  12,  1993,  DRI  informed  institutional  officials  at  The 
Cleveland  Clinic  Foundation  of  its  intent  to  open  a  case  (DRI  93- 
28)  and  to  conduct  a  direct  investigation  into  the  alleged 
scientific  misconduct  involving  The  Cleveland  Clinic  Foundation 
COMS  program.   The  institution  was  instructed  not  to  initiate  its 
own  inquiry  or  investigation  and  to  secure  all  research  and 
medical  records  of  every  patient  affiliated  with  the  COMS 
progreim.   Based  on  the  Coordinating  Center  report  and  their 
positions  with  regard  to  the  COMS  project,  DRI  named  the  possible 
respondents  in  the  matter. 

The  DRI  site  visit  to  The  Cleveland  Clinic  Foundation  COMS  center 
was  conducted  on  December  6-9,  1993.   Medical  and  research  files 
of  the  24  eligible  patients  enrolled  in  The  Cleveland  Clinic 
Foundation  COMS  program  and  of  37  patients  screened  but  not 
eligible  for  the  COMS  program  were  evaluated  for  possible 
fabrication  and/or  falsification  of  reported  data.   COMS 
Coordinating  Center  staff  provided  technical  support  during  this 
review.   Key  witnesses  and  all  respondents  were  interviewed  and 
their  testimony  recorded. 

The  DRI  has  concluded  its  fact-finding  of  The  Cleveland  Clinic 
Foundation  COMS  program  and  is  preparing  its  final  report. 

ORI  has  briefed  the  Office  of  the  Inspector  General,  HHS  on  DRI 
#93-27  and  #93-28.   Additionally,  ORI  met  with  officials  from  NEI 
on  April  19,  1994  to  brief  them  on  the  status  of  the  cases.   At 
that  meeting,. ORI  and  NEI  staff  agreed  that  a  letter  would  be 
sent  by  NEI  to  all  COMS  patients  regarding  the  investigations. 
NEI  confirmed  that  this  letter  had  been  sent  to  every  patient  by 
April  29.   NEI  has  also  prepared  a  statement  which  will  be 
published  in  the  May  18  issue  of  the  Journal  of  the  American 
Medical  Association. 

Potential  compliance  issues  concerning  the  reporting  of 
scientific  misconduct  to  the  ORI  and  the  termination  of 
employment  prior  to  an  inquiry/ investigation  remain  to  be 
assessed. 

B.    Inquiry  into  possible  falsification  and  fabrication  of  data 
in  the  PES  funded  ISCHEMIC  OPTIC  NEUROPATHY  DECOMPRESSION 
TRIAL  at  Ohio  State  University  (DRI  94-04) 

The  Ischemic  Optic  Neuropathy  Decompression  Trial  (lONDT)  is 
another  multicenter  clinical  trial  supported  by  the  NEI.   The 
purpose  of  the  trial  is  to  assess  the  safety  and  efficacy  of 
optic  nerve  sheath  decompression  surgery  for  non-arteric  ischemic 
optic  neuropathy  (NAION) .   NAION  is  the  most  common  cause  of 
acute  optic  nerve  disease  in  older  persons  and  causes  permanent 


90 


and  severe  visual  loss.   It  is  estimated  that  6,100  new  cases  of 
NAION  are  seen  each  year.   The  lONDT  is  a  randomized  clinical 
trial  designed  to  compare  the  difference  in  change  in  visual 
acuity  at  six  months  in  patients  assigned  to  either  surgery  or 
careful  followup.   Begun  in  November  1992,  the  trial  has  26 
participating  centers. 

On  Wednesday  April  6,  1994,  the  Director,  lONDT  Coordinating 
Center,  University  of  Maryland  at  Baltimore,  notified  the  NEI 
program  officer  and  misconduct  officer  and  also  called  the 
Division  of  Research  Investigations  (DRI)  to  report  possible 
misrepresentations  of  information  concerning  subjects  in  the 
trial  provided  to  the  Coordinating  Center  by  members  of  the 
project  team  at  Ohio  State  University  (OSU) .   The  lONDT  project 
at  OSU  has  received  funding  from  PHS  under  a  cooperative 
agreement . 

During  a  December  1993  site  visit,  numerous  protocol  violations 
had  been  observed  and  a  decision  was  made  to  closely  monitor  the 
OSU  contributions.   During  the  recent  site  visit  (April  4,  1994), 
the  coordinating  center  staff  uncovered  discrepancies  in 
infonnation  that  was  provided  regarding  randomization  of  subject 
027-15  and  about  subjects'  visual  acuity  measurements  at 
randomization  (baseline)  which  raised  the  possibility  that  data 
had  been  falsified  or  fabricated. 

From  information  sent  from  the  Coordinating  Center  on  April  8, 
1994,  concerning  the  visual  acuity  measurements  at  baseline  for 
some  of  the  OSU  patients,  DRI  indicated  to  OSU  officials  that  an 
inquiry  would  likely  be  necessary.   The  Coordinating  Center  sent 
DRI  a  copy  of  a  draft  site  visit  report  on  the  evening  of  Friday, 
April  8. 

The  specific  allegations  of  scientific  misconduct  as  formulated 
by  DRI  are  that: 

1)  an  individual  or  individuals  at  OSU  falsified  or 
fabricated  information  provided  to  the  lONDT 
Coordinating  Center; 

2)  falsified  information  regarding  randomization  of 
subject  #027-15  was  reported  verbally  to  Coordinating 
Center  staff  during  the  April  4,  1994,  site  visit; 

3)  visual  acuity  scores  of  patients  randomized  to  either 
careful  watching  or  surgery  were  fabricated  or 
falsified. 

DRI  requested  that  OSU  conduct  an  inquiry  on  April  11,  1994. 
University  of  Maryland  officials  were  also  notified  of  this 
decision  because  the  continuing  cooperation  of  Coordinating 
Center  staff  in  providing  materials,  information  and  possibly 
technical  support  would  be  required. 


91 

Mr.  DiNGELL.  Grentlemen,  we've  kept  you  here  a  long  time.  I 
want  to  say  a  couple  things.  The  NIH  is  a  national  treasure  and 
you  are  guardians  of  a  national  treasure.  It's  one  that  this  commit- 
tee and  the  chairman  of  this  subcommittee  and  this  subcommittee, 
my  good  friend,  Mr.  Schaefer,  have  most  actively  supported  and  we 
intend  to  continue  doing  that. 

You  have  had  a  long  and  a  difficult  appearance  before  the  com- 
mittee. I  want  to  make  it  very  clear  to  you,  Dr.  Varmus,  and  to 
you.  Dr.  Broder,  that  I  have  immense  respect  for  you  both.  And  I 
want  to  make  it  very  clear  that  I  think  that  the  comments  that  you 
have  made  today  with  regard  to  the  attitude  and  the  behavior  of 
NIH  and  NCI  with  regard  to  scientific  misconduct,  the  protection 
of  participants  in  trials  and  tests  and  research  studies  that  are 
funded  by  your  agency  have  been  most  helpful  and  are  important. 

I  want  you  to  know  that  we've  long  been  critical  of  science  and 
there's  been  a  long  effort  on  the  part  of  this  subcommittee  to  see 
to  it  that  government  money  is  properly  spent,  that  the  protection 
of  participants  in  trials  and  tests  and  studies  is  adequate,  the  in- 
formation available  to  them  is  at  a  level  that  you  and  I  would  like 
to  see  them  have,  and,  also,  to  see  to  it  that  the  public  moneys  are 
well  spent  and  that  the  factual  results  of  the  studies  are  factually 
reported,  and  that  there's  not  misbehavior  in  terms  of  fraudulent 
studies  or  falsification  of  data  or  information  and  so  forth. 

It's  been  a  long  and  hard  and  difficult  task.  We  found  today  a 
new  component  which  is  now  very  clear,  and  that  is  it's  not  just 
an  isolated  question  in  which  science  will  rectify  the  falsification  or 
the  improprieties  with  regard  to  data  and  collection  of  information, 
but,  rather,  that  human  lives  are  at  stake. 

We  sense  that  there  is  a  great  awareness  on  your  part,  Dr. 
Varmus  and  Dr.  Broder.  I  am  content  to  continue  to  work  with  you 
and  to  watch  and  see  to  it  that  the  kind  of  effort  that  you  are  mak- 
ing, which  is  significantly  different  and  better  than  your  prede- 
cessors, including  one  of  your  most  immediate  predecessors.  Dr. 
Varmus,  and  to  see  to  it  that  you  succeed  in  your  efforts  to  make 
this  system  work  better  for  the  benefit  of  all  of  us,  that  the  tax- 
payers' money  be  better  spent,  that  the  protection  be  afforded  to 
the  participants,  that  the  information  be  such  as  to  give  an  honest 
appraisal  so  that  people  can  make  proper  judgments  with  regard 
to  their  personal  activities,  as  Ms.  Sigal  has  indicted  to  us. 

So  as  we  close  the  hearing,  I  want  to  express  my  thanks  to  you 
both  and  also  to  Dr.  Chabner,  Dr.  Friedman,  Dr.  Bivens,  for  your 
assistance.  You've  got  over  there  a  very  nasty  job.  Doctor,  and  as 
for  you.  Dr.  Varmus  and  Dr.  Broder,  because  occasionally  you've 
got  to  address  the  question  of  scientific  behavior  within  and  with- 
out the  institution  and  whether  or  not  it  conforms  with  what  I 
think  we  regard  as  being  the  necessary  tests.  That  is  that  science 
should  be  the  pursuit  of  truth  and  that  it  should  be  honestly  con- 
ducted, with  minimal  risk  and  hazard  to  those  who  innocently  par- 
ticipate in  these  studies,  and  that  the  factual  results  should  be  that 
which  add  to  our  knowledge  and  which  increase  the  safety  and  the 
protection  of  those  who  pay  for  it,  and  that  the  public  money 
should  be  properly  spent. 

I  think  that  you  and  I  look  forward  to  a  time  when  we're  going 
to  be  able  to  work  better  together.  If  things  have  happened  today 


92 

which  cause  you  distress,  you  have  my  expression  of  sorrow  and 
apology. 

I  want  you  to  understand  that  we're  going  to  try  and  work  with 
you.  We  expect  good  things  from  you.  We  know  that  you  were  en- 
gaged in  a  difficult  task  and,  as  I've  indicated,  the  communication 
to  the  public  of  potential  wrongdoing  of  a  colleague  or  a  scientist, 
particularly  one  who  might  happen  to  be  a  famous  name  or  well 
known  and  influential  figure  in  science,  is  always  difficult.  It's 
fraught  with  peril  to  you,  possible  lawsuits  and  other  difficulties. 

We  understand  that  it  takes  time  to  refine  the  procedures  that 
you  have  so  that  you  can  do  this  thing  properly.  We  will  work  with 
you  to  get  you  both  the  time  and  a  climate  in  which  you  may  do 
these  things  with  minimum  peril  to  yourself  and  greater  success 
from  the  standpoint  of  the  great  undertaking  of  which  you  are  a 
part. 

So  you  have  our  thanks  and  our  good  wishes  and  we  will  look 
forward  to  working  with  you.  We  will  also  look  forward  to  the  next 
hearing  in  this  matter,  which  will  be  occurring,  I  suspect,  in  the 
not  far  future  involving  the  University  of  Pittsburgh. 

Having  said  those  things,  we  express  to  you  our  thanks  and  our 
good  wishes,  gentlemen,  and  thank  you  for  being  with  us  today. 

The  subcommittee  will  stand  adjourned  till  the  call  of  the  Chair. 

[Whereupon,  at  2:15  p.m.,  the  subcommittee  adjourned,  to  recon- 
vene at  the  call  of  the  Chair.] 

[The  following  letter  was  received:] 


93 

ZENECA 


1800  Concord  Pike 
Wilmington 
Delaware  19897  USA 

Telephone  (302)  886  775  1 
Fax  (302)  886-7688 


Phermaceuticals  Group 


Alan  J.  Milbauer 
Vice  President 
External  Affairs 


April  20,    1994 

The  Honorable  John  D.  Dlngell 
Chairman,  Subconnittee  on  Oversight  and 

Investigations 
Coanittee  on  Energy  and  Commerce 
Room  2323  Raybum  Hotise  Office  Building 
Washington,  D.C.  20515 

Dear  Hr.  Chairman: 

I  an  writing  respectfully  to  request  a  correction  of  the  record  concerning 
an  issue  which  was  raised  in  the  Oversight  and  Investigations  Subconnittee ' s 
April  13  hearing  on  breast  cancer  research. 

In  the  course  of  the  Subcommittee's  hearing,  an  internal  Zeneca  memorandum 
(dated  July  7,  1993),  which  we  provided  to  the  Subcommittee,  was  quoted  from 
and  discussed.  In  questions  you  asked  of  Dr.  Broder  of  the  National  Cancer 
Institute  (NCI),  it  was  implied  that  this  memorandum  proved  that  the  NCI  had 
not  been  notified  in  a  timely  way  of  information  Zeneca  had  received 
concerning  the  number  of  patients  within  the  B-I4  trial  who  were  developing 
endometrial  cancer  while  on  NOLVADEX. 

This  is  simply  not  true.   In  fact,  the  memorandum  cited  in  the  hearing 
summarizes  a  conference  call  which  was  held  between  Dr.  Leslie  Ford  of  the 
NCI,  Dr.  Fisher  of  the  NSABP  and  Dr.  Paul  Plourde  of  Zeneca  to  discuss  the 
endometrial  cancer  issue  and  the  need  to  modify  the  label  on  NOLVADEX.  This 
conference  call  was  initiated  by  Dr.  Plourde  as  soon  as  the  endometrial 
cancer  information  came  to  his  attention.   Furthermore,  another  document  we 
provided  to  your  subcommittee  was  a  copy  of  a  July  8,  1993  letter  from  Dr. 
Plourde  to  Dr.  Fisher  of  the  NSABP  and  Dr.  Ford  of  the  NCI.  This  letter 
discusses  the  findings  concerning  endometrial  cancer  and  Zeneca's  proposed 
amendments  to  the  prescribing  information  for  NOLVADEX.  Finally,  on  June 
30,  1993,  Zeneca  also  notified  the  FDA  of  these  findings  and  of  the  proposed 
labeling  changes. 

These  documents  are  clear:  As  soon  as  Zeneca  obtained  information 
concerning  the  increased  incidence  of  endometrial  cancer  in  the  B-14  trial, 
we  alerted  the  NCI  and  made  appropriate  changes  to  the  prescription 
information  for  NOLVADEX.   In  short,  Zeneca  acted  promptly  and  responsibly. 

I  appreciate  this  opportunity  to  correct  the  record  concerning  the 
unfortunate  implication  that  Zeneca  was  somehow  deficient  in  reporting 
information  to  the  NCI.   I  respectfully  request  that  this  letter  and  the 
accompanying  attachments  be  entered  into  the  record  of  the  April  13  hearing. 


Sinceraiy, 


Ian  J 
AJM/gfi 
Attachments 


94 
i,tNtC_/\     Pharmaceuticals  Group 


Internal  Heinorandum  ZENECA,  INC. 

UILMINGTON,  DE  19897 
CLINICAL  &  MEDICAL  AFFAIRS 
ENDOCRINOLOCT 

TO:      SEE  ATTACHED  LISTING 

DATE:    JULY  7,  1993 

FROM:    PAUL  V.  PLOURDE,  M.D.  CC: 

RE:      CONVERSATION  WITH  DR.  FISHER  (NSABP)  &  DR.  FORD  (NCI) 

PRIVILEGE  AND  CONFIDENTIAL:   ATrORNET-CLIENT  INFORMATION 

Today  on  July  7,   1993,  at  1:30  p.a.  I  called  Dr.  Fisher  to  infora  hla  on  the 
company's  position  on  the  association  of  endoaetrial  cancer  vith  NOLVADEX 
treataent. 

I  first  discussed  vith  Dr.  Fisher  that  ve  over  the  last  fev  veeks  have  been 
looking  at  the  association  of  endoaetrial  cancer  vith  NOLVADEX  treataent. 
This  vas  in  part  initiated  because  of  the  Tale  publication  reporting  that  the 
tuaors  associated  vith  NOLVADEX  treataent  vere  poorly  differentiated  tuaors 
resulting  in  a  poor  prognosis  for  these  patients.  Our  evaluation  froa  the 
clinical  trial  data  base  as  veil  as  froa  the  literature  could  not  confira  this 
Tale  publication.  Therefore,  ve  did  not  feel  that  ve  needed  to  aake  any 
changes  in  our  label.  Hovever,  viligence  is  necessary  and  ve  vill  continue  to 
aonitor  this  closely.  Dr.  Fisher  thought  that  this  vas  appropriate  and  he 
hiase}f  has  Initiated  soae  activity  vithin  the  NSABP  to  explore  this  further. 
Be  is  requesting  that  slides  froa  the  endoaetrial  cancer  seen  in  the  B-14 
trial  be  evaluated.  He  plans  on  doing  this  over  the  next  several  aonths. - 

I  then  proceeded  to  tell  Or.  Fisher  that  the  increasing  nuaber  of  patients 
vithin  the  B-14  trial  developing  endoaetrial  cancer  vhile  on  NOLVADEX  did 
proapt  us  to  look  at  this  issue  aore  closely.  Upon  careful  reviev  of  the 
data,  ve  felt  that  there  vas  an  Increase  risk  to  develop  endoaetrial  cancer 
vith  NOLVADEX  and  that  ve  vill  aodify  our  label  to  reflect  this.  I  also 
coaaented  that  it  vas  iapossible  to  precisely  quantitate  the  relative  risk 
although  qualitatively  it  did  appear  that  there  vas  a  slight  increase 
incidence.  Or.  Fisher  agreed  vith  this  assessaent  and  felt  that  ve  vere 
acting  responsible  by  changing  our  label.  I  coaaented  to  hla  that  at  least  in 
the  United  States,  ve  vould  have  to  aake  ainor  changes  to  our  label  but  I  did 
not  see  these  changes  having  a  great  iapact  on  the  treataent  of  patients  vith 
confiraed  breast  cancer  and  also  on  the  US  prevention  trial  since  the  protocol 
did  include  the  B-14  data  as  veil  as  the  Swedish  data  and  that  this  potential 
risk  vas  noted  on  the  consent  fora.   Hovever,  I  did  coaaent  that  it  did  have 
aore  of  an  iapact  on  the  European  trial  vhlch  vould  require  that  the  protocol 
and  consent  fora  be  aodified.   Or.  Fisher  vas  told,  that  Dr.  Cusick  has  been 
notified  and  the  European  protocol  and  consent  vill  be  aodified. 

AbwtMwu  wn««rfnMC.  - 
*ie*w«ei  HMCCA  ^^*-»*  • . 


95 


CONFIDENTIAL 

Page  2 

Conversation  with  Or.  Fisher 

Dr.  Fisher  appreciated  our  willingness  to  provide  hin  vith  a  copy  of  the 
justification  document  for  this  label  change.  Dr.  Fisher  did  coinnent  about 
the  potential  negative  publicity  that  could  occur.  In  particular,  this  could 
be  the  bullet  being  sought  by  the  health  authority  in  the  UK  to  stop  the 
European  prevention  trial.  If  that  is  the  case,  that  vould  have  a  major 
effect  in  the  United  States.  Be  agreed  that  ve  should  be  prepared  for  this 
potential  negative  outcome. 

I  told  him  that  ve  vould  be  gathering  a  panel  of  experts  in  endometrial  cancer 
together  vithin  the  next  tvo  or  three  months.  This  vould  be  an  intematlonal 
panel  composed  of  the  prevention  trial  investigators,  epidemiologist  and 
gynecologists.  Dr.  Fisher  did  not  see  the  great  need  for  having  this  panel, 
since  he  felt  that  the  issue  had  been  examined  and  he  sav  no  need  to  rediscuss 
this  issue.  Hovever,  he  understood  our  desire  to  convene  this  panel  and 
agreed  to  participate. 

I  also  Informed  him  that  ve  did  not,  as  a  company,  see  that  the  risks  had 
changed  appreciably  to  varrant  discontinuation  of  medication  to  the  NCI. 
Dr.  Fisher  vas  relieved  vith  that  decision. 

I  also  informed  him  of  Dr.  Cuzick's  plan  to  hold  a  press  conference  this 
coming  Friday  morning.  He  vas  quite  surprised  about  the  press  conference 
although  he  did  knov  that  Dr.  Cuzick  vas  having  an  investigators  meeting  that 
day.  Or.  Cuzick  had  requested  an  NSABP  representative  to  attend  this  meeting. 
The  NSABP  due  to  time  constraints,  vas  unable  to  send  anyone  and  Dr.  Cuzick 
then  called  Dr.  Ford  at  the  NCI  and  it  vas  agreed  that  Or.  Susan  Nayfield  from 
the  NCI  vas  to  represent  the  US.  Dr.  Fisher  and  Dr.  Ford  vere  unavare  that  a 
press  conference  vas  going  to  be  held. 

I  told  Dr.  Fisher  that  I  vanted  to  call  the  NCI  and  Inform  him  of  these 
changes.  He  insisted  that  he  call  Dr.  Ford  to  discuss  the  Issues,  but  finally 
he  agreed  to  have  a  conference  call  vith  Dr.  Ford. 


Later  this  same  day,  a  conference  call  vas  held  betveen  Dr.  Leslie  Ford  from 
the  NCI  and  Dr.  Fisher  from  the  NSABP.  Dr.  Fisher  had  briefed  Dr.  Ford  on  the 
issues  that  ve  had  discussed  above.  Dr.  Ford  had  no  comments  and  agreed  vith 
our  approach  in  re^rds  to  the  label  change.  She  did  not  feel  that,  the  US 
needed  to  make  any  changes  in  the  consent  form  or  the  protocol  since  the 
endometrial  cancer  Issue  that  had  already  had  been  addressed  consistant  vith 
our  nev  label  change.   She  recognized  hovever,  that  this  could  cause  some 
unnecessary  and  inappropriate  publicity.  Vith  this.  Dr.  Ford  did  have 
concerns  about  Dr.  Nayfield  being  in  the  UK  during  the  press  conference  and 
the  meeting.  She  vill  be  contacting  Dr.  Nayfield  to  alert  her  of  our 
intention  to  modify  our  label.  Or.  Nayfield  vill  be  instructed  not  to 
participate  in  the  press  conference. 


96 


CONFIDENTIAL 

Page  3 

Conversation  vith  Dr.  Fisher 


Dr.  Ford  also  told  me  that  the  MRC  had  recently  approved  the  protocol  this 
veek.  This  needs  to  be  confiraed,  but  if  true,  this  vould  ainiaize  the  inpact 
of  Cuzick's  press  conference,   (i.e.,  the  UK  Health  Authority  may  not  be  in  a 
position  to  be  embarrassed  as  vas  originally  feared). 

I  discussed  the  panel  of  experts  to  be  organized  to  revlev  the  data.  Both 
£elt  that  this  vas  unnecessary.  She  informed  me  that  as  far  the  Prevention 
Trial,  a  sub-study  vlll  be  conducted  where  endometrial  sampling  vill  be  done 
periodically  during  the  trial. 

I  told  Drs.  Ford  and  Fisher  that  I  vould  be  sending  them  a  copy  of  the 
Justification  document  and  that  they  should  hold  this  document  as  confidential 
information.  I  also  informed  them  that  I  vould  be  glad  to  send  them  a  copy  of 
the  specific  wording  change  ve  are  recommending  as  a  label  change  for  their 
information. 

Overall,  this  interaction  vas  positive  and  I  believe  that  both  groups  felt 
happy  that  ve  vere  keeping  them  informed. 

PVP:«c 


97 


ENECA 

i.O,.„l!-..l..|-ii4r^..|!|.| 


ICOO  Co-icC'-c  i'.-  ■ 
VVilmmgion 
Delawate  19S97    U5^ 


July  8,    1993 


Bernard  Fisher,  H.D. 
University  of  Pittsburgh 
School  of  Hediclne 
914  Scaife  Ball 
3SS0  Terrace  Street 
Pittsburgh,  PA  15261 

Dear  Drs.  Fisher  and  Ford: 


Leslie  Ford,  M.D. 
National  Cancer  Institute 
Room  300 

Executive  Plaza  North 
Bethesda,  MD  20892 


Further  to  our  telephone  conversation  last  week,  I  enclose  a  copy  of 
the  report  vhich  ve  have  prepared  for  discussion  vitb  regulatory 
authorities  to  support  our  proposal  to  aaend  the  prescribing 
inforaatlon  for  NOLVADEX  vith  respect  to  endonetrial  changes,  vith 
particular  reference  to  endonetrial  cancer.  Although  I  assuae  that 
you  vill  vlsh  to  discuss  the  contents  of  the  report  vith  your  clinical 
colleagues  of  the  NSABP  and  MCI,  it  Is  a  condition  of  this  disclosure 
to  you  that  the  Groups  treat  the  data  as  confidential  and  does  not 
disclose  the  contents  of  the  report  to  any  third  party. 

ZENECA  Pharaaceuticals  believe  that  the  inforaation  currently 
available  strengthens  the  association  betveen  NOLVADEX  and  an 
increased  incidence  of  endonetrial  cancer,  and  that  this  does 
therefore  inpact  on  the  assessnent  of  the  risk  benefit  ratio  for  vomen 
participating  in  the  current  prevention  trials. 

Ve  are  therefore  inforalng  all  3  groups  (US,  Italy  in  addition  to  UK) 
of  this  inforaation  as  one  of  the  conditions  governing  our  agreenent 
to  supply  clinical  trial  aedication  i.e.  that  ve  vould  infora  the 
groups  of  any  significant  inforaation  relevant  to  tanoxifen  as  and 
vhen  it  becaae  available  during  the  course  of  the  studies.  In  turn  ve 
require  that  each  group  nov  ensures  that  this  increased  risk  is 
appropriately  reflected  in  the  trial  protocol  and  consent  fora  and 
that  adequate  aeasures  are  in  place  for  aonitoring  the  occurrence  of 
endonetrial  changes  during  the  trial. 

Although  the  NSABP  PI  protocol  and  consent  forn  does  address  this 
issue,  I  vould  ask  that  you,  upon  reviev  of  this  docuaent,  re-exaaine 
if  both  the  protocol  or  consent  fora  needs  to  be  amended. 

I  nust  remind  you  that  the  continued  supply  of  trial  aedication  to  the 
NCI  depends  upon  the  adoption  of  these  aeasures. 


98 


Page  2 

Drs.    Fisher  and  Ford 


As  I  nentioned  on  the  phone,   ve  believe   that   it  vould  be  appropriate 
to  convene  a  workshop  Involving  not  only  representatives  of   the  3 
prevention  trials  but  also  a  nunber  of  independent  experts  in  the 
fields  of  epideaiology,   breast  cancer  and  gynecology,  so  that  ve  can 
discuss  together  the  impact  of  the  information  available  on 
risk-benefit  assessment  for  vomen  participating  in  these  trials.     Ve 
vill  be  progressing  this  over  the  next  2-3  months.     In  the  meantime, 
obviously  ve  felt  it  very  important  that  you  see  this  information. 


B«st  regards. 
Sincerely, 


Paul  V.  Plourde,  M.D. 
Director,  Endocrine  Resemrch 


PVP:mc 


99 


nrrERNAL  kemorardun 

ZENECA  Pharmaceuticals  Group 
ntm  30-Jun-1993  lOsSOaa  EOT     Dni^  Ragulatory  Affalra 

Ttltphon*  (302)886-2127 
TOt      Sc«  Bclov 

nUMi    Anthoay  F.  Rogart 

SUBJICTi  FDA  CONTACT-NOLVAOBZ 

AT  10 1 20  TODAY  I  00NTACT8D  MR.  PAUL  ZIMMERMAN  (FOA-CSO)  TO  ADVISB  HM  OF  THE 
FOLLOVINGt 

1-OBS  ISSUE I  SEHBCA  IS  PREPARING  A  DOCUMENT  VHICH  PROVIDES  ALTERNATITB 
LANGOAGB  AND  JUSTIFICATION.  THIS  DOCUMENT  VILL  BE  AVAILABLE  LATE  NEXT 
VEER  AND  I  WILL  CALL  BIN  VHEN  I  RBdEVE  IT.   EB  AGREED. 

2-ENDO  CBANGBSi  BASED  ON  CURRENT  RBVIBV  OF  DATA  ZBHBCA  VILL  MODIFY  THE  PIB  TO 
UPDATE  TBB  LANGUAGE  DBSOUBING  ENDOMETRIAL  CHANGES.  BE  ASK  FOR  THE  LANGUAGE 
AND  I  READ  TO  HIM  THE  PROPOSED  BID  STRESSING  TBAT  IT  WAS  DRAFT  AMD  COULD 
CHANGE  BUT  THE  MESSAGE  VOULO  NOT.  I  ALSO  STATED  TBAT  DR.  PLOURDB  VILL  CALL  Oft. 
nSHBR  UTBR  IN  TBB  DAT  TO  ADXVSB  HIM  OF  TBB  LABEL  CHANGE.  BE  ASKED  IF 
ANYTHHIG  VILL  CHANGE  REGARDING  THE  PREVBHnOM  TRIAL.  I  SAID  TBAT  OUR  POSITION 
IS  THAT  TBB  RISK/BENEFIT  RATIO  FOR  BREAST  CANCER  TRBATMBNT  DOBS  NOT  C8AM3  AND 
THAT  THE  FRBVBNnON  TRIAL  S0OUID  CONTINUE  BUT  TBAT  VAS  CK.  FISHER'S  DECISION. 
VB  BELIEVE  TBAT  TBB  ISSUE  OF  BRDOMBTRIAL  FIMDIN68  OPPOSITB  NOLVADU  TRBATMBNT 
SAVE  BEEN  PROFERLT  ASSESSED  IN  THE  DBLIBBRATIOHS  REGARDING  TBB  PRBVBNTIOH 
TRIAL  AND  TBAT  TBB  LABEL  CBAN6B  SISBNGBTEMS  TBB  LANGUACB  IN  THE  PIB.  BE  ASKED 
IF  EBNBa  VAS  GOING  TO  DO  ANYTBING  FUKTBER  REGARDING  TBI8  ISSUE.  I  APVI8BD 
TBAT  IN  THE  NEAR  FUTURE  VB  VILL  OOHVENE  A  PANEL  OF  EXPERTS  TO  REVIEV  THE  DATA 
AND  TBAT  I  VILL  ADVISB  PDA  VEEN  TBI8  VILL  TAKE  PUCE.  BE  SAID  TBAT  HE  VILL 
ADVISB  nt.  JUSTICE  (FDA-MEDICAL  RBVIBVBR)  OF  THE  LABEL  CHANGE.  I  TOLD  MR.  I 
TBAT  IF  TDk  NBBOBD  ANYMHtl  SVC  TO  CONTACT  ME.  BE  AGBB8D. 

TONT 

Distrlkotlaoi 

TOi  Jack  6.  IHineaa 
JU  O'Sbaa 
Donald  R.  Vard 
Orlando  Caasar 
Jaffragr  A.  Separ 
Stavan  B.  Laipart 
Rabaeea  D.  Cintran,  M.O. 
*      Paul  V.  Plourda 
Karan  S.  Linaa 
Vllllan  C.  Loena 
Vllllan  J.  Kannady 
Banish  Canaroa 
Jaany  Bolnaa 
Ronald  L.  Rrall 


SCIENTIFIC  MISCONDUCT  IN  BREAST 
CANCER  RESEARCH 


WEDNESDAY,  JUNE  15,  1994 

House  of  Representatives, 
Committee  on  Energy  and  Commerce, 
Subcommittee  on  Oversight  and  Investigations, 

Washington,  DC. 

The  subcommittee  met,  pursuant  to  notice,  at  10  a.m.,  in  room 
2123,  Rayburn  House  Office  Building,  Hon.  John  D.  Dingell  (chair- 
man) presiding. 

Mr.  Dingell.  The  subcommittee  will  come  to  order. 

In  April  of  this  year,  the  subcommittee  held  a  hearing  on  a  series 
of  issues  involving  the  University  of  Pittsburgh's  and  Dr.  Bernard 
Fisher's  mismanagement  of  and  the  National  Cancer  Institute's 
failure  to  oversee,  some  of  the  Nation's  most  important  clinical 
trials  involving  the  treatment  and  prevention  of  breast  cancer. 
Some  of  the  issues  discussed  at  that  hearing  included  the  falsifica- 
tion and  fabrication  of  data  at  St.  Luc  Hospital  in  Montreal,  Can- 
ada; the  failure  of  the  University  of  Pittsburgh,  Dr.  Fisher,  and 
NCI  to  deal  with  the  fraud  in  a  timely  manner;  the  failure  of  Dr. 
Fisher,  NCI,  and  the  Office  of  Research  Integrity  (ORI)  to  inform 
the  women  of  America  of  the  fraud  for  nearly  3  years;  Dr.  Fisher's 
failure  to  publish  a  reanalysis  of  the  data,  which  was  required  to 
be  done  because  of  the  need  to  exclude  the  fraudulent  St.  Luc  data 
excluded;  the  failure  of  Dr.  Fisher  to  inform  NCI,  Zeneca,  which  is 
the  pharmaceutical  manufacturer  of  tamoxifen,  and  the  American 
women  in  a  timely  manner  about  the  endometrial  cancer  deaths 
due  to  tamoxifen;  and  the  failure  of  Dr.  Fisher  and  his  colleagues 
to  inform  NCI  about  audit  findings  revealing  significant  data  irreg- 
ularities at  a  second  Montreal  hospital,  St.  Mary's. 

These  multiple  and  serious  failings  came  to  a  head  in  March  of 
this  year,  when  the  media  broke  the  news  and  the  American  public 
finally  learned  what  NCI,  the  University  of  Pittsburgh,  and  Dr. 
Fisher  should  have  told  them  long  ago.  And  yet,  these  revelations 
are  only  a  part  of  a  long  story. 

First,  new  problems  have  been  disclosed  at  several  additional 
sites.  In  March  1994,  NCI  found  reports  of  audits  conducted  in  No- 
vember 1992  at  Tulane  and  LSU.  These  National  Surgical  Adju- 
vant Breast  and  Bowel  Project  reports,  that  is,  NSABP  reports, 
prepared  one  year  following  the  audits,  revealed  serious  and  chron- 
ic problems  of  missing  and  misrepresented  data.  In  fact,  the  major- 
ity of  the  data  at  these  two  sites  could  not  be  located. 

(101) 


102 

After  two  further  NCI  audits  at  these  two  sites,  significant  ques- 
tions remained  about  the  completeness  and  the  accuracy  of  the 
data.  And  the  audit  process  continues. 

In  two  other  instances,  the  subcommittee  identified  audit  re- 
ports, one  dating  from  1990  and  one  from  1992,  both  of  which  re- 
vealed very  significant  discrepancies  and  irregularities.  At  Memo- 
rial Cancer  Research  Foundation,  the  NSABP  auditor  reported, 
among  numerous  other  items,  that,  "A  serious  problem  has  been 
identified  with  this  institution  with  respect  to  the  accuracy  of  the 
data  reported  to  the  NSABP  at  the  time  of  randomization."  Fur- 
ther, the  NSABP  audit  report  cited  a  "serious  problem"  at  the  site 
because,  and  I  quote  again,  "IRB,  Institutional  Review  Board,  will 
not  approve  or  reapprove  the  NSABP  protocols." 

At  South  Nassau  Communities  Hospital,  two  of  eight  patients  re- 
ported as  eligible  were  found  by  the  audit  to  be  clearly  ineligible 
due  to  their  medical  history.  The  auditor  recommended,  and  I 
quote,  "additional  randomization  be  suspended  from  this  institution 
until  such  time  as  the  principal  investigator  and  his  associates  de- 
velop procedures  which  ensure  eligibility,  treatment,  and  follow-up 
of  all  patients  entered  into  NSABP  protocols." 

Curiously,  neither  of  these  problem-ridden  audits  received  any 
effective  follow-up.  Indeed,  in  the  case  of  the  Memorial  Cancer  Re- 
search Foundation,  the  original  audit  report  was  found  in  a  file 
drawer  at  Pittsburgh.  The  report  had  never  been  sent  to  NCI  or  to 
the  research  site. 

The  NCI  recently  completed  an  audit  at  the  Foundation,  and  as 
a  result,  NCI  has  referred  the  site  for  formal  investigations  of  sci- 
entific misconduct  and  violation  of  Department  of  Health  and 
Human  Services  regulations  for  the  protection  of  human  research 
subjects. 

As  for  South  Nassau,  contrary  to  NSABP's  claims  to  NCI,  it  was 
not  suspended.  No  effort  has  been  made  to  determine  how  wide- 
spread the  observed  discrepancies  were.  Neither  was  any  effort 
made  to  determine  if  patients  had  been  harmed  by  their  entry  into 
protocols  for  which  they  were  not  eligible.  Further  reviews  of  South 
Nassau  are  now  pending. 

Moreover,  the  subcommittee's  review  of  hundreds  of  audit  reports 
revealed  that,  in  many  cases,  NSABP  was  years  behind  in  perform- 
ing audits  and  in  writing  up  and  forwarding  audit  reports  after  the 
audits  were  completed.  More  significantly,  the  follow-up  to  identi- 
fied audit  deficiencies  was  all  but  nonexistent. 

NSABP  itself  has  recently  begun  to  review  its  own  past  audits 
and  reported  several  dozen  sites  with  major  discrepancies  that 
have  not  been  resolved  yet.  Dr.  Fisher  and  his  colleagues  have 
claimed  this  was  due  to  a  lack  of  resources  for  an  adequate  audit 
staff.  They  claimed  that  they  asked  for  additional  resources  from 
NCI,  but  were  turned  down.  NCI  says  that  this  is  not  so. 

The  revelations  prior  to  and  at  the  April  hearing,  as  well  as  sub- 
sequently, have  triggered  a  number  of  further  developments: 

Dr.  Fisher  has  been  removed  as  head  of  NSABP; 

Some  of  Dr.  Fisher's  top  colleagues  at  the  University  of  Pitts- 
burgh, under  the  cloak  of  anonymity,  started  what  appears  to  have 
been  an  ill-advised  letter- writing  campaign.  They  were  demanding 
an  investigation  of  the  NCI  Director,  Dr.  Samuel  Broder,  and  the 


103 

reinstatement  of  Dr.  Fisher,  even  in  the  face  of  mounting  evidence 
of  significant  management  failures; 

At  the  recommendation  of  NCI,  the  Office  of  Research  Integrity 
has  directed  Pittsburgh  to  conduct  an  inquiry  to  determine  if  a  sci- 
entific misconduct  investigation  is  warranted  involving  the  actions 
of  Dr.  Fisher  and  others  at  NSABP; 

And  the  grant  for  the  overall  administration  of  NSABP  will  be 
recompeted  next  year. 

The  senior  vice  chancellor  for  health  sciences  at  the  University 
of  Pittsburgh  told  the  subcommittee  staff  he  believes  there  is  a  cul- 
ture in  the  scientific  community  of  inappropriate  deference  to  the 
superstars  of  science.  He  believes  that  this  culture  has  resulted  in 
numerous  institutions  failing  to  carry  out  their  lawful  responsibil- 
ities in  overseeing  the  work  and  actions  of  prominent  scientists. 
The  University  of  Pittsburgh  now  says  that  this  culture  of  def- 
erence was  a  significant  factor  in  its  failure  to  oversee  the  work  of 
Dr.  Fisher. 

This  same  problem  has  become  apparent  to  a  number  of  other  in- 
stitutions and  has  been  found  in  a  number  of  other  questions  ex- 
amined by  this  subcommittee.  We  hope  that  the  scientific  commu- 
nity as  a  whole  will  come  to  recognize  that  this  is  a  serious  prob- 
lem. 

Second,  for  years  there  have  been  questions  about  the  role  of 
pharmaceutical  company  funds  in  clinical  research.  Here,  very  sub- 
stantial sums  of  money,  with  little  or  no  accounting  for  the  expend- 
iture of  that  money,  passed  from  Zeneca  to  NSABP,  and  to  the  Uni- 
versity of  Pittsburgh.  It  will  be  noted  that  a  precise  accounting  has 
not  been  obtained  from  any  of  the  parties. 

In  turn,  the  manufacturer  gained  substantial  benefits  via  even- 
tual food  and  drug  approvals,  publicity,  and  similar  events.  The  es- 
timated figures  show  that  Zeneca  gave  the  University  of  Pittsburgh 
some  $600,000  for  a  chair  for  Dr.  Fisher.  Zeneca  also  gave  NSABP 
about  $600,000  for  their  semiannual  meetings.  Zeneca  also  sup- 
plied to  NSABP  about  $300,000  for  other  purposes.  This  is  a  total 
of  over  $1.5  million,  plus  the  substantial  cost  of  supplying  the 
tamoxifen  drug  free  of  charge  for  the  trials. 

Essentially,  at  the  same  time  the  audit  program  was  floundering, 
Zeneca  was  providing  huge  sums  of  money,  not  for  audit  resources, 
but  for  lavish  parties  and  receptions  at  NSABP's  semiannual  meet- 
ings. These  meetings  were  held  in  splendid  places  around  the  Unit- 
ed States  and  Canada.  For  example,  the  meetings  were  in  places 
which  imposed  severe  hardship  on  attendees  such  as  the  Doral 
Country  Club;  Banff  Springs  Hotel  in  the  Canadian  Rockies;  Cha- 
teau Frontenac  in  Quebec  City;  the  Fairmont  Hotel  in  San  Fran- 
cisco; Hilton  Head,  S.C;  Vancouver,  British  Columbia;  Palm 
Springs,  Calif.;  DisneyWorld  and  Bal  Harbour,  Fl. 

Some  of  the  receptions  included,  among  other  things,  strolling 
troubadours,  wine-tasting  parties,  fire  dances,  live  steel  bands,  and 
fine  food,  champagne,  and  dance.  At  Bal  Harbour,  they  touted  an 
elegant  evening  at  the  seashore  with  premium  hard  liquor,  beer, 
and  wine.  A  number  of  these  receptions  cost  up  to  $80,000  apiece. 
Curiously,  in  1991,  the  entire  NSABP  audit  function  was  carried 
out  on  a  budget  of  a  little  more  than  $80,000. 


104 

Third,  today  we  will  hear  about  the  failure  to  report  in  a  timely 
manner  the  deaths  from  endometrial  cancer  of  patients  receiving 
tamoxifen  in  Dr.  Fisher's  studies.  We  will  also  examine  the  matter 
of  informed  consent  for  the  tamoxifen  prevention  study.  While  this 
study  was  in  progress  and  after  Dr.  Fisher  and  his  colleagues 
learned  of  at  least  two  deaths  in  the  study,  deaths  ultimately  prov- 
en to  be  due  to  endometrial  cancer,  a  sentence  was  added  to  the 
informed  consent  that  said,  and  I  quote  now,  "No  deaths  from 
endometrial  cancer  have  been  reported."  This  sentence  was  not  re- 
moved from  the  consent  form  until  1994,  at  which  time  Dr.  Fisher 
had  learned  of  the  death  of  at  least  four  persons  related  to 
endometrial  cancer. 

We  look  forward  to  hearing  Dr.  Fisher's  account  and  explanation 
of  these  matters. 

In  concluding  the  opening  statement,  the  Chair  wants  to  remind 
all  of  us  of  what  is  most  important  in  this  affair.  This  matter  is 
part  about  failed  responsibility.  It  is  part  about  failures  of  scientific 
integrity.  But  above  all,  the  question  that  should  concern  us  most 
is  the  welfare  of  the  thousands  of  women  who,  at  some  considerable 
risk  to  themselves,  committed  their  lives  and  health  to  these  stud- 
ies. 

The  fact  that  thousands  of  women  were  involved,  the  fact  that 
statistical  power  was  so  great  that,  overall,  the  conclusions  may  not 
be  changed,  does  not  mitigate  the  sacrifice  of  the  women  who  were 
entered  into  studies  for  which  they  were  not  eligible  or  for  which 
they  did  not  give  consent  or  on  which  they  were  not  properly  in- 
formed. It  does  not  compensate  for  the  risks  these  women  faced, 
only  to  have  their  data  discarded  due  to  abject  sloppiness,  gross 
negligence  or  even  fraud. 

As  we  proceed  today,  the  Chair  reminds  us  all  that  it  behooves 
us  to  be  mindful  of,  and  to  honor,  these  women. 

The  Chair  recognizes  the  gentleman  from  Ohio. 

Mr.  Brown.  Thank  you,  Mr.  Chairman.  I  want  to  thank  you 
again  for  holding  this  follow-up  hearing  on  scientific  fraud  in  feder- 
ally funded  breast  cancer  research.  It  is  obviously  an  important 
issue  that  warrants  this  subcommittee's  and  this  Congress's  imme- 
diate attention. 

What  is  it  we  are  really  talking  about  today?  We  are  talking 
about  the  health  and  well-being  of  our  wives,  our  mothers,  our 
daughters.  Women  all  over  America  are  doubting  their  choices  and 
questioning  their  health  decisions.  We  owe  it  to  them  to  give  them 
answers  on  which  they  can  depend. 

Unfortunately,  we  are  currently  stuck  in  a  holding  pattern.  With 
each  new  audit,  it  appears  there  is  new  information  about  bad  or 
missing  data,  about  inappropriate  enrollment  of  women  in  the 
study,  about  inaccurate  reporting  and  follow-up.  In  a  study  of  this 
magnitude,  at  some  point  you  are  likely  to  encounter  a  few  simple 
errors  in  the  collection  of  information.  However,  the  extent  to 
which  there  have  been  errors  and  to  which  there  have  been  false 
data  uncovered  is  alarming;  and  I  believe  it  calls  for  complete  in- 
vestigation. 

In  addition,  it  is  clear  that  NSABP  has  been  quite  lax  in  its  own 
auditing  to  ensure  clean  and  useful  information. 


105 

Mr.  Chairman,  I  don't  believe  that  any  of  us  wants  to  bring  down 
the  scientific  establishment  or  damage  the  reputation  of  NSABP. 
At  the  same  time,  we  owe  it  to  all  women  to  ensure  that  the  infor- 
mation they  use  in  consultation  with  their  physicians  is  truthful, 
is  reliable,  and  is  up  to  date. 

Thank  you,  Mr.  Chairman. 

Mr.  DiNGELL.  The  time  of  the  gentleman  has  expired. 

The  Chair  recognizes  now  the  distinguished  gentleman  from  Col- 
orado, the  Ranking  Minority  Member  of  the  committee,  for  such 
opening  statement  as  he  chooses. 

Mr.  SCHAEFER.  Thank  you,  Mr.  Chairman.  As  the  subcommittee 
and  the  chairman  know,  I  began  our  April  hearing  on  this  matter 
by  stating  that  we  must  seek  to  reassure  the  American  people 
about  the  soundness  of  American  science.  Two  months  have  passed, 
and  although  we  have  made  some  progress  towards  this  goal,  we 
still  have  a  lot  to  accomplish. 

Thanks  to  your  leadership,  Mr.  Chairman,  this  subcommittee 
acted  promptly  in  exploring  the  circumstances  surrounding  re- 
search activities  of  the  NSABP.  It  did  so  in  a  calm,  professional 
manner  because,  while  it  is  vital  that  we  uncover  fraud  and  mis- 
management, it  is  also  essential  that  we  calm  the  fears  of  Amer- 
ican women  who  relied  on  the  studies  in  this  question. 

We  are  relieved  to  learn  that  the  basic  results  of  the  study  con- 
taining falsified  data  have  since  been  verified  by  subsequent  analy- 
sis. I  am  troubled,  however,  to  find  that  the  problems  outlined  at 
our  April  hearing  were  more  the  rule  rather  than  the  exception. 

The  subcommittee  staff  has  done  a  terrific  job  in  uncovering 
these  problems.  It  has  learned  that  extensive  reporting  problems 
across  the  United  States  and  Canada  existed.  The  NSABP  did  send 
competent  and  able  auditors  into  the  field,  it  seems.  However,  it 
failed  to  act  upon  the  information  received  from  its  audit  teams, 
neither  generating  appropriate  reports  nor  notifying  the  institu- 
tions of  potential  problems. 

This  situation  was  unacceptable  in  April  and  it  certainly  is 
today.  The  Food  and  Drug  Administration  and  the  NCI  have  al- 
lowed breast  cancer  prevention  trials  to  resume;  and  while  I  agree 
this  research  is  definitely  important,  given  the  track  record  of 
NSABP,  I  have  very,  very  serious  concerns. 

Now,  Mr.  Chairman,  I  look  forward  to  hearing  what  actions  have 
been  taken  by  the  University  of  Pittsburgh  since  our  last  hearing, 
as  well  as  learning  what  the  National  Cancer  Institute  has  done 
in  light  of  the  testimony  this  subcommittee  received. 

This  hearing  is  not  about  an  institution  or  research  program,  it 
is  about  millions  of  American  women  who  have  a  right  to  be  able 
to  rely  on  scientific  and  medical  information  given  to  them  by  their 
government;  and  that  is  why  these  hearings  are  so  important,  Mr. 
Chairman.  I  certainly  applaud  you  for  continuing  this  effort. 

Yield  back. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman. 

The  Chair  wants  to  observe  that  the  staffs  of  the  Minority  and 
the  subcommittee  have  worked  very  closely  on  this  matter,  as  they 
always  do,  and  I  want  to  express  my  appreciation  to  my  friend 
from  Colorado  and  to  his  very  able  staff  for  their  assistance  in  this 
matter. 


106 

The  gentlewoman  from  Pennsylvania. 

Ms.  Margolies-Mezvinsky.  Thank  you,  Mr.  Chairman,  thank 
you  for  having  these  hearings  and  continuing  to  do  so. 

Mr.  Chairman,  I  would  like  to  thank  you  for  all  that  you  have 
done  with  regard  to  the  National  Surgical  Adjuvant  Breast  Project. 
The  NSABP  is  an  important,  federally  funded  program  which  was 
designed  to  study  treatments  for  breast  cancer  and  bowel  cancer, 
as  we  know.  I  am  pleased  that  we  will  be  hearing  from  several  im- 
portant witnesses  today  regarding  their  role  in  the  recently  discov- 
ered auditing  problems  with  the  program. 

The  question  on  all  women's  minds  is  whether  the  conclusions  of 
these  studies  should  be  trusted.  I  want  to  make  sure  that  we  can 
assure  women  across  this  country  that  underlying  recommenda- 
tions for  treatment  of  breast  cancer  have  not  changed.  Instead,  this 
hearing  will  focus  on  problems  with  breast  cancer  programs  and 
will  ensure  that  in  the  future  such  mistakes  will  not  be  made 
again. 

I  think  that  we  have  some  fundamental  questions  that  must  be 
answered,  and  I  hope  that  they  will  be  answered  here  today;  that 
is,  how  did  it  happen,  how  can  we  prevent  this  from  happening 
again,  how  can  we  in  general  be  more  vigilant,  and  how  can  we  an- 
swer questions  for  folks  like  Jill  Sigal,  who  is  in  the  audience  here 
today,  when  she  asked,  can  women  who  choose  lumpectomy  over 
mastectomy  be  comfortable  with  their  decisions? 

I  look  forward  to  hearing  from  the  panel.  Thank  you  once  again, 
Mr.  Chairman,  for  holding  these  hearings. 

[The  opening  statement  of  Ms.  Margolies-Mezvinsky  follows:] 

Statement  of  Hon.  Marjorie  Margolies-Mezvinsky 

Mr.  Chairman,  I  would  like  to  thank  you  for  holding  this  second  hearing  on  the 
National  Surgical  Adjuvant  Breast  Project  (NSABP).  The  NSABP  is  an  important 
Federal  funding  program  which  was  designed  to  study  treatments  for  breast  cancer 
and  bowel  cancer.  I  am  pleased  that  we  will  hear  from  severeil  important  witnesses 
today  regarding  their  role  in  the  recently  discovered  auditing  problems  with  the  pro- 
gram. 

The  question  on  all  women's  minds  is  whether  the  conclusions  of  these  studies 
should  be  trusted.  I  want  to  assure  women  across  America  that  the  underlying  rec- 
ommendations for  treatment  of  breast  cancer  have  not  changed.  Instead,  this  hear- 
ing will  focus  on  problems  with  breast  cancer  program  and  will  ensure  that,  in  the 
future,  such  mistakes  will  not  be  made  again. 

I  am  pleased  that  there  will  four  panels  testifying  today,  including  representatives 
from  Zeneca  Pharmaceuticals,  Dr.  Bernard  Fisher,  the  former  director  of  NSABP, 
representatives  from  the  University  of  Pittsburgh,  and  Dr.  Samuel  Broder,  Director 
of  the  National  Cancer  Institute. 

In  the  past  few  months,  we  have  heard  press  accounts  of  several  serious  auditing 
problems  with  certain  sites  in  these  studies.  These  auditing  problems  seem  to  be 
pervasive  in  certain  sites  of  the  study.  I  am  disturbed  that  the  information  about 
faulty  data  was  not  shared  with  the  National  Cancer  Institute  in  a  more  timely 
manner.  I  understand  that  new  procedures  have  been  put  into  place  to  ensure  that 
this  detections  of  faulty  data  will  be  given  to  both  the  National  Cancer  Institute, 
the  NSABP,  and  officials  with  Zeneca.  All  parties  must  be  fully  informed  of  any 
problems  to  ensure  that  women  can  trust  the  result  of  these  trials. 

In  addition,  I  am  pleased  that  the  National  Cancer  Institute  is  conducting  its  own 
auditing  procedures  to  determine  if  further  problems  there  are  in  the  NSABP.  These 
confirmations  of  previous  auditing  are  necessary  to  ensure  the  soundness  of  the  con- 
clusions of  clinical  trials. 

Finally,  I  am  pleased  that  the  clinical  preventive  trials  on  tamoxifen  have  been 
restarted.  Many  women  are  interested  in  the  results  of  these  preventive  trials.  I  be- 
lieve that  the  Congress  must  continue  to  be  vigilant  to  ensure  that  proper  auditing 
standards  are  being  applied  to  all  clinical  sites.  It  is  my  understanding  that  a  new 


107 

auditing  system  will  be  used  in  these  preventive  trials  to  ensure  that  all  women  in 
these  trials  have  been  given  a  consent  form,  that  their  clinical  information  has  been 
confirmed,  and  that  proper  precautions  are  being  taken  to  prevent  further  abuses 
in  this  vital  research  project. 

I  look  forward  to  learning  more  about  this  situation  and  will  continue  to  be  vigi- 
lant in  my  efforts  to  assert  the  facts  regarding  this  research  project.  The  women  of 
America  deserve  to  know  the  facts,  and  I  will  make  sure  that  those  facts  are  avail- 
able to  them. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentlewoman  for  her  opening 
statement. 

The  Chair  announces  that  the  first  panel  will  be  composed  of  Dr. 
John  Patterson,  M.D.,  international  medical  director,  Zeneca  Phar- 
maceuticals Group,  accompanied  by  Dr.  Paul  Plourde,  senior  direc- 
tor, clinical  and  medical  affairs,  Zeneca  Pharmaceuticals  Group, 
and  Alan  Milbauer,  vice  president,  external  affairs,  Zeneca  Phar- 
maceuticals Group. 

Gentlemen,  welcome  to  the  subcommittee. 

Gentlemen,  as  you  are  no  doubt  aware,  it  is  the  practice  of  this 
subcommittee  that  all  witnesses  testify  under  oath.  Do  any  of  you 
object  to  so  doing? 

The  Chair  advises  that,  given  the  fact  that  you  are  testifying 
under  oath,  it  is  your  right  to  be  advised  by  counsel.  Do  any  of  you 
desire  to  be  advised  by  counsel  during  your  appearance  here? 

Very  well,  then  gentlemen  for  your  information,  copies  of  the 
rules  of  the  committee,  the  subcommittee  and  the  House  of  Rep- 
resentatives are  there  in  the  red  and  the  blue  booklets  before  you 
at  the  table. 

Gentlemen,  if  you  have  no  objection,  then,  to  testifying  under 
oath,  would  you  please  each  rise  and  raise  your  right  hand. 

[Witnesses  sworn.] 

Mr.  DiNGELL.  Gentlemen,  you  may  each  consider  yourself  under 
oath.  We  will  recognize  you  starting  with  Dr.  Patterson;  then.  Dr. 
Plourde  and  Mr.  Milbauer,  you  will  be  recognized  for  such  state- 
ments as  you  choose  to  give.  Gentlemen,  proceed. 

TESTIMONY  OF  JOHN  PATTERSON,  INTERNATIONAL  MEDICAL 
DIRECTOR,  ZENECA  PHARMACEUTICALS  GROUP,  ACCOM- 
PANIED BY  PAUL  PLOURDE,  SENIOR  DIRECTOR,  CLINICAL 
AND  MEDICAL  AFFAIRS,  AND  ALAN  MILBAUER,  VICE  PRESI- 
DENT, EXTERNAL  AFFAIRS 

Mr.  Patterson.  Thank  you,  Mr.  Chairman.  Mr.  Chairman  and 
members  of  the  subcommittee,  I  am  Dr.  John  Patterson,  inter- 
national medical  director  of  Zeneca"  Pharmaceuticals,  working  at 
our  company's  headquarters  in  the  United  Kingdom.  Joining  me 
today  are  Dr.  Paul  Plourde,  senior  director  of  clinical  and  medical 
affairs,  and  Alan  Milbauer,  vice  president,  external  affairs,  at 
Zeneca  Pharmaceuticals  Group,  both  based  in  Wilmington,  Dela- 
ware. Zeneca  is  a  bioscience-based  business,  formerly  a  part  of  Im- 
perial Chemical  Industries,  or  ICI. 

Our  company  is  proud  of  its  history  of  dedication  to  scientific  re- 
search and  patient  support  in  the  field  of  women's  health.  Zeneca 
is  the  discoverer,  developer  and  manufacturer  of  Nolvadex,  the 
world's  leading  drug  for  the  treatment  of  breast  cancer  and  the 
world's  most  prescribed  anticancer  medicine.  Nolvadex  is  our  trade 
name  for  tamoxifen.  Since   1973,  millions  of  patients  have  taken 


108 

tamoxifen  as  an  important  component  of  their  breast  cancer  treat- 
ment. 

In  recent  months,  there  has  been  considerable  press  regarding 
tainted  data  in  breast  cancer  trials  conducted  by  NSABP.  It  is  un- 
derstandable that  patients  are  wondering  if  the  medical  basis  for 
choosing  their  treatment  is  correct.  They  have  also  heard  that  the 
risk  of  developing  uterine  cancer  as  a  side  effect  of  treatment  with 
tamoxifen  is  greater  than  previously  thought,  and  they  wonder  how 
that  risk  applies  to  them.  Additionally,  they  have  witnessed  a  heat- 
ed public  debate  over  the  merits  of  the  use  of  tamoxifen  to  prevent 
breast  cancer  in  healthy  women  who  are  at  high  risk  of  developing 
this  deadly  disease. 

We  are  concerned  that  public  confusion  over  these  issues  could 
lead  patients  with  breast  cancer  to  be  afraid  of  tamoxifen,  a  medi- 
cation with  the  demonstrated  ability  to  delay  recurrence  of  their 
disease  and  prolong  their  lives. 

Mr.  Chairman  and  members  of  the  subcommittee,  let  me  be  very 
clear:  For  treatment  of  breast  cancer,  tamoxifen  is  one  of  the  most 
studied  drugs  in  the  world.  Its  safety  and  efficacy  for  this  purpose 
is  very  well  established.  With  over  6  million  patient-years  of  expe- 
rience in  more  than  20  years  of  clinical  use  around  the  world, 
tamoxifen  continues  to  be  a  key  weapon  in  the  battle  against 
breast  cancer. 

In  patients  with  early-stage  breast  cancer,  tamoxifen  reduces  the 
risk  of  recurrence  of  the  disease  after  10  years  by  up  to  Va,  and  it 
reduces  the  odds  of  death  by  20  percent.  Further,  clinical  trials  of 
patients  with  early  breast  cancer  have  also  demonstrated  a  marked 
reduction  in  new  cancers  affecting  the  other  breast  in  women  treat- 
ed with  tamoxifen. 

In  summary,  the  proven  benefits  of  tamoxifen  in  the  treatment 
of  breast  cancer  in  men  and  women  outweigh  its  risks.  It  is  my 
hope  that  these  hearings  will  underscore  this  indisputable  fact. 

As  an  anticancer  agent,  tamoxifen  is  a  powerful  medicine,  and  in 
recent  years,  an  increased  risk  of  developing  uterine  cancer  has 
been  reported  in  women  who  are  taking  it.  Zeneca  has  closely  mon- 
itored the  incidence  of  uterine  cancers,  both  from  clinical  trials  and 
spontaneous  reports.  We  have  promptly  reported  the  data  to  the 
FDA  and  have  also  presented  it  to  independent  experts  for  evalua- 
tion. 

Starting  in  1989,  Zeneca  has  amended  its  U.S.  label  on  four  dif- 
ferent occasions  as  new  information  about  the  risk  of  uterine  can- 
cer was  received.  We  have  recent  data  collected  from  14  studies  in- 
volving nearly  17,000  women  worldwide.  They  indicate  that  the  in- 
creased risk  of  uterine  cancer  associated  with  tamoxifen  is  approxi- 
mately 20  times  smaller  than  the  more  deadly  risk  that  breast  can- 
cer will  recur  or  spread  if  patients  do  not  take  tamoxifen. 

Much  has  been  made  in  the  press  about  reports  of  uterine  cancer 
deaths  in  the  large  B-14  trial  involving  tamoxifen  in  breast  cancer 
patients  being  conducted  by  NSABP.  To  obtain  accurate,  long-term 
information,  the  women  who  participate  in  this  trial  are  followed 
until  they  die.  Thus,  reports  of  deaths  are  an  expected  component 
of  cancer  clinical  trials;  and  it  is  a  sad  fact,  Mr.  Chairman,  that 
even  with  a  potentially  curable  tumor  such  as  uterine  cancer,  some 
women  contracting  this  cancer  will  die  of  it. 


109 

We  have  been  informed  that  one  of  the  subjects  of  today's  hear- 
ing will  be  the  timeliness  of  reports  about  four  uterine  cancer 
deaths  that  occurred  in  the  B-14  trial.  The  first  of  those  deaths  oc- 
curred on  June  25,  1991.  Zeneca  was  informed  of  that  death  on 
February  10,  1992,  in  a  routine  NSABP  report.  The  cause  of  death 
was  not  clearly  stated,  and  several  potential  causes  were  listed 
which  included  uterine  cancer. 

We  reported  this  case  to  the  Food  and  Drug  Administration  on 
April  1,  1992.  NSABP  reported  the  remaining  three  uterine  cancer 
deaths  to  Zeneca  on  December  13,  1993,  and  we  reported  these  to 
FDA  on  January  5,  1994.  According  to  the  subcommittee  staff,  the 
NSABP  apparently  has  claimed  that  it  notified  Zeneca  of  one  of 
these  deaths  on  February  1,  1993. 

In  fact,  NSABP  provided  Zeneca  with  a  large  data  set,  including 
data  that  reflected  that  death,  but  no  cause  of  death  was  specified 
in  that  data.  It  was  not  until  December  1993  that  Zeneca  learned 
from  NSABP  that  this  death  was,  in  fact,  due  to  uterine  cancer.  In- 
deed, NSABP's  own  August  1993  report  to  its  membership  failed  to 
identify  any  uterine  cancer  death  in  any  patient. 

The  B-14  uterine  cancer  deaths  have  brought  into  question  the 
wisdom  of  continuing  tamoxifen  in  the  prevention  trial.  I  want  to 
make  it  clear  to  this  committee  that  Zeneca  is  not  sponsoring  or 
endorsing  the  tamoxifen  breast  cancer  prevention  trial.  This  trial 
is  sponsored  by  the  National  Cancer  Institute  and  is  being  con- 
ducted by  NSABP.  A  brief  history  of  the  genesis  of  the  prevention 
trial  may  be  helpful  to  the  committee. 

In  1985,  Zeneca  was  strongly  encouraged  by  a  significant  number 
of  scientists  in  the  medical  community  to  sponsor  a  tamoxifen 
breast  cancer  prevention  trial.  We  responded  by  organizing  a  con- 
ference involving  leading  experts  in  medical  oncology,  animal  toxi- 
cology, and  epidemiology.  The  consensus  was  that  additional  data 
were  required  before  an  informed  decision  could  be  made  on  the  ap- 
propriateness of  the  prevention  trial.  As  additional  data  became 
available,  Zeneca  provided  it  both  to  regulatory  authorities  and  the 
scientific  community. 

In  1990,  members  of  the  academic  community  again  approached 
Zeneca  about  a  possible  prevention  trial.  The  company  reiterated 
its  concerns.  However,  following  many  discussions,  the  National 
Cancer  Institute,  the  FDA,  and  medical  experts  decided  that  the 
potential  risks  and  benefits  put  together — that  the  benefits  out- 
weighed the  risks  and  that  a  study  of  tamoxifen  in  prevention 
should  be  conducted. 

Zeneca,  then  the  sole  supplier  of  tamoxifen  in  the  United  States, 
subsequently  agreed,  at  NCI's  request,  to  provide  tamoxifen  tablets 
and  matching  placebo  for  the  study.  The  tablets  were  supplied  free 
of  charge  on  the  understanding  that  participants  were  to  be  prop- 
erly monitored  and  fully  informed  of  the  potential  risks.  NSABP 
also  agreed  to  notify  Zeneca  of  any  significant  new  findings  in  the 
study. 

We  have  been  informed  that  another  subject  of  today s  hearing 
will  be  Zeneca's  financial  relationships  with  the  University  of  Pitts- 
burgh and  the  NSABP.  Let  me  assure  you,  Mr.  Chairman,  that  our 
relationship  with  the  University  and  NSABP  was  at  all  times  prop- 
er and  consistent  with  applicable  legal,  ethical,  and  moral  stand- 


110 

ards.  Any  insinuation  to  the  contrary  is  completely  false.  I  have 
outlined  the  full  extent  of  these  relationships  in  my  written  state- 
ment to  the  subcommittee. 

In  summary,  pajrments  were  made  by  Zeneca  to  NSABP  for  three 
categories  of  work;  namely,  data  processing  and  management,  sup- 
port for  meetings,  activities,  and  honoraria  and  travel  costs  to  Drs. 
Fisher  and  Redmond  in  respective  appearances  at  FDA  and  sci- 
entific meetings.  In  addition,  Zeneca  agreed  to  partly  fund,  at  the 
request  of  the  University  of  Pittsburgh,  a  chair  in  the  Department 
of  Surgery  at  Pittsburgh.  Zeneca's  conduct  in  this  respect  was  en- 
tirely consistent  with  both  the  spirit  and  letter  of  FDA  policy  and 
the  codes  of  conduct  adopted  by  the  American  Medical  Association 
and  the  Pharmaceutical  Research  Manufacturers  Association,  not 
to  mention  our  own  internal  corporate  guidelines,  as  they  applied 
then  and  as  they  apply  now. 

We  believe  that  our  financial  assistance  to  the  University  of 
Pittsburgh  and  NSABP  contributed  to  breast  cancer  research  in  the 
United  States  and  fostered  a  better  understanding  of  breast  cancer 
treatment  around  the  world.  We  do  not  believe  that  this  financial 
support  caused  NSABP  to  be  less  diligent  in  reporting  safety  infor- 
mation regarding  tamoxifen.  In  fact,  much  of  our  financial  support 
was  given  specifically  to  obtain  extra  safety  reports  to  submit  to 
the  Food  and  Drug  Administration  and  to  facilitate  the  exchange 
of  information  amongst  breast  cancer  researchers. 

In  conclusion,  Mr.  Chairman,  we  at  Zeneca  are  committed  to  the 
development  and  support  of  safe  medicines  backed  by  good  science 
and  proper  scientific  practices.  We  believe  that  tamoxifen  is  a  safe 
and  effective  medicine  vital  to  the  treatment  of  breast  cancer.  We 
deplore  fraud  and  poor  scientific  practices  in  clinical  research.  We 
accordingly  are  pleased  to  assist  the  subcommittee  in  this  inves- 
tigation. 

Thank  you  for  the  opportunity  to  speak.  My  colleagues  and  I 
would  now  be  happy  to  answer  your  questions. 

[The  prepared  statement  of  Dr.  Patterson  follows:] 


Ill 


STATEMENT   OF   JOHN  PATTERSON 

Mr.  Chairman  and  Members  of  the  Subcommittee,  I  am  Dr.  John  Patterson, 
International  Medical  Director  of  Zeneca  Pharmaceuticals,  working  at  our  company's 
headquarters  in  the  United  Kingdom.  Joining  me  today  are  Dr.  Paul  Plourde,  Senior 
Director  of  Clinical  and  Medical  Affairs,  and  Alan  Milbauer,  Vice  President  External 
Affairs  at  Zeneca  Pharmaceuticals  Group,  both  based  in  Wilmington,  Delaware.   Zeneca  is  a 
bioscience  based  business,  formerly  a  part  of  Imperial  Chemical  Industries,  or  ICI. 

Our  company  is  proud  of  its  history  of  dedication  to  scientific  research  and  patient 
support  in  the  field  of  women's  health.   Zeneca  is  the  discoverer,  developer  and 
manufacturer  of  Nolvadex,  the  world's  leading  drug  for  the  treatment  of  breast  cancer  and 
the  world's  most  prescribed  anticancer  medicine.   Nolvadex  is  our  trade  name  for  tamoxifen. 
Since  1973,  millions  of  patients  have  taken  tamoxifoi  as  an  important  component  of  thdr 
breast  cancer  treatment 

In  recent  months,  there  has  been  considerable  press  regarding  tainted  data  in  breast 
cancer  clinical  trials  conducted  by  NSABP.  It  is  understandable  that  patients  are  wondering 
if  the  medical  basis  for  choosing  their  treatment  is  correct.  They  have  also  heard  that  the 
risk  of  developing  uterine  cancer  as  a  side  effect  of  treatment  with  tamoxifen  is  greater  than 
was  previously  thought,  and  they  wonder  how  this  risk  applies  to  them.   Additionally,  they 
have  witnessed  a  heated  public  debate  over  the  merits  of  the  use  of  tamoxifen  to  prevent 
breast  cancer  in  healthy  women  who  are  at  high  risk  of  developing  this  deadly  disease.   We 
are  concerned  that  public  confusion  over  these  issues  could  lead  patients  with  breast  cancer  to 


112 


2 


be  afraid  of  tamoxifen,  a  medication  with  the  demonstrated  ability  to  delay  recurrence  of 
their  disease  and  prolong  their  lives. 

Mr.  Chairman  and  Members  of  the  Subcommittee,  let  me  be  very  clean  For 
treatment  of  breast  canc^,  tamoxifen  is  one  of  the  most  studied  drugs  in  the  world.  Its 
safety  and  efficacy  for  this  purpose  are  very  well  established.  With  over  six  million  patient- 
years  of  experience  in  more  than  20  years  of  clinical  use  around  the  world,  tamoxifen 
continues  to  be  a  key  wes^n  in  the  battle  against  breast  cancer.   In  patients  with  early  stage 
breast  cancer,  tamoxifen  reduces  the  risk  of  recurrence  of  the  disease  after  10  years  by  up  to 
one  third,  and  reduces  the  odds  of  death  by  20%.    Further,  clinical  trials  of  patients  with 
early  breast  cancer  have  also  demonstrated  a  marked  reduction  in  new  cancers  affecting  the 
other  breast  in  women  treated  with  tamoxifen.   Data  also  suggest  that  tamoxifen  may 
decrease  cardiovascular  disease  and  stabilize  postmenopausal  bone  loss.   In  summary,  the 
proven  benefits  of  tamoxifen  in  the  treatment  of  breast  cancer  in  men  and  women  outweigh 
its  risks.  It  is  my  hope  that  these  hearings  will  underscore  this  indisputable  £act 

As  an  anticancer  agent,  tamoxifen  is  a  powerful  medicine  and,  in  recent  years,  an 
increased  risk  of  developing  uterine  cancer  has  been  reported  in  women  who  are  taking  it 
Zeneca  has  closely  monitored  the  incidence  of  uterine  cancers  both  from  clinical  trials  and 
spontaneous  reports.   We  have  promptly  reported  that  data  to  the  FDA  and  have  also 
presented  it  to  independent  experts  for  evaluation.   Starting  in  1989,  Zeneca  has  amended  its 
label  on  four  different  occasions  as  new  information  about  the  risk  of  uterine  cancer  was 
received.   We  have  recent  data  collected  from  14  studies  involving  nearly  17,000  women. 
They  indicate  that  the  increased  risk  of  uterine  cancer  associated  with  tamoxifen  is 


113 


3 
q}pFO]uinately  20  times  smaller  than  the  more  deadly  risk  that  breast  cancer  will  recur  or 

spread  if  patients  do  not  take  tamoxifen. 

Much  has  been  made  in  the  press  about  tepoits  of  uterine  cancer  deaths  in  the  large 
B-14  trial  involving  tamoxifen  in  breast  cancer  patients  that  is  being  conducted  by  NSABP. 
To  obtain  accurate,  long-term  information,  the  women  who  participate  in  this  trial  are 
followed  until  they  die.  Thus,  rqwrts  of  deaths  are  an  ejq>ected  component  of  cancer  clinical 
trials,  and  it  is  a  sad  fact  that,  even  with  a  potentially  curable  tumor  such  as  uterine  cancer, 
some  women  contracting  this  cancer  will  die. 

We  have  been  informed  that  one  of  the  subjects  of  today's  hearing  will  be  the 
timeliness  of  rqxirts  about  four  uterine  cancer  deaths  that  occurred  in  the  B-14  trial.  The 
first  of  those  deaths  occurred  on  June  25,  1991.   Zeneca  was  informed  of  that  death  on 
Fd}ruary  10,  1992  in  a  routine  NSABP  rqx)rt.  The  cause  of  death  was  not  clearly  stated 
and  several  potential  causes  were  listed  including  uterine  cancer.  We  rqrarted  this  case  to 
the  FDA  on  April  1,  1992.  NSABP  rqwrted  the  remaining  three  uterine  cancer  deaths  to 
Zeneca  on  Decemb»  13,  1993.  We  reported  these  deaths  to  tfie  FDA  on  January  5,  1994. 
According  to  the  Subcommittee  staff,  the  NSABP  apparently  has  claimed  that  it  notified 
Zeneca  of  one  of  these  deaths  on  February  1,  1993.   In  fact,  NSABP  provided  Zeneca  with  a 
data  set  reflecting  that  death,  but  no  cause  of  death  was  specified.   It  was  not  until  £>ecember 
1993  that  Zeneca  learned  from  NSABP  that  this  death  was  due  to  uterine  cancer.   Indeed, 
NSABP's  own  August  1993  report  failed  to  identify  any  uterine  cancer  death  in  any  patient 

The  B-14  uterine  cancer  deaths  have  brought  into  question  the  wisdom  of  continuing 
the  tamoxifen  prevention  trial.   I  want  to  make  it  clear  that  Zeneca  is  not  sponsoring  or 


114 


4 

endorsing  the  tamoxifen  breast  cancer  prevention  trial.   This  trial  is  sponsored  by  the 

National  Cancer  Institute  (NCI)  and  is  being  conducted  by  NSABP.   A  brief  history  of  the 
genesis  of  the  prevoition  trial  may  be  helpful: 

In  1985,  Zeneca  was  strongly  encouraged  by  a  significant  number  of  scientists  in  the 
medical  community  to  sponsor  a  tamoxifen  breast  cancer  prevention  trial.   Zeneca  responded 
by  organizing  a  conference  involving  leading  experts  in  medical  oncology,  animal  toxicology 
and  epidemiology.   The  consensus  was  that  additional  data  were  required  before  an  informed 
decision  could  be  made  on  the  appropriateness  of  a  prevention  trial. 

As  additional  data  became  available,  Zeneca  provided  it  to  regulatory  authorities  and 
the  scientific  commimity.   In  1990,  members  of  the  academic  community  approached  Zeneca 
again  about  a  possible  prevention  trial.   The  company  reiterated  its  concerns.   Following 
many  discussions,  the  NCI,  the  FDA  and  medical  experts  decided  that  the  potential  benefits 
of  prevention  outweighed  the  risks  and  that  a  study  of  tamoxifen  in  prevention  should  be 
conducted. 

Zeneca,  then  the  sole  supplier  of  tamoxifen  in  the  United  States,  subsequently  agreed, 
at  NCI's  request,  to  provide  tamoxifen  tablets  and  matching  placebo  for  the  study.  The 
tablets  were  supplied  free  of  charge  on  the  understanding  that  participants  were  to  be 
properly  monitored  and  fiilly  informed  of  the  potential  risks.    NSABP  agreed  to  notify 
Zeneca  of  any  significant  new  findings. 

As  a  company,  Zeneca  has  a  major  commitment  to  research  not  only  on  breast  cancer 
but  also  on  other  conditions  that  affect  women's  health.   We  have  participated  and  will 
continue  to  participate  in  all  appropriate  discussions  of  the  scientific  issues  and  facts  that 


115 


5 
have  a  bearing  on  the  prevention  and  treatment  of  breast  cancer. 

We  have  been  informed  that  another  subject  of  today's  hearing  will  be  Zeneca's 
relatiooshq)  with  the  University  of  Pittsburgh  and  the  NSABP.  Let  me  assure  you  that  our 
relationship  with  the  University  and  the  NSABP  was  at  all  times  proper  and  consistent  with 
applicable  legal,  ethical  and  moral  standards.   Any  insinuation  to  tiie  contrary  is  completely 
false.  I  would  like  to  outline  for  the  Subcommittee  the  full  extent  of  these  relationships. 

Zeneca  first  developed  a  working  relationship  with  NSABP  in  the  mid-1970's,  after 
tamoxifen  had  been  approved  for  use  in  the  U.K.  but  before  it  had  been  introduced  in  the 
United  States.  When  NSABP  approached  us  regarding  the  use  of  tamoxifen  in  trials,  they 
were  one  of  the  leading  breast  cancer  research  groups  in  the  world,  with  an  unequalled 
rq>utation  for  conducting  large  scale  cancer  clinical  trials. 

Over  diese  nearly  twenty  years,  the  NSABP  has  conducted  a  large  number  of  trials  on 
tamoxifen,  all  of  which  were  developed,  funded,  s^roved  and  conducted  under  the  auspices 
of  the  NCI.  With  the  excq)tion  of  the  prevaition  trial,  all  previous  NSABP  tamoxifen 
studies  have  been  undertaken  with  large  groups  of  women  who  have  been  diagnosed  and 
treated  surgically  for  breast  cancer. 

Starting  in  1982,  we  contracted  with  the  NSABP  to  obtain  data  from  the  trials  they 
were  conducting  on  tamoxifen.  These  data  were  used  to  support  our  applications  to  the  FDA 
for  new  indications  for  tamoxifen  and  to  comply  with  FDA  safety  and  monitoring 
requirements.    Since  1982,  payments  from  Zeneca  to  NSABP  for  the  cost  associated  with 
data  management,  analyses  and  reports  on  studies  of  tamoxifen  have  totaled  approximately 
$200,000.   An  additional  $73,000  was  paid  for  work  done  on  tamoxifen  at  the  University  of 


116 


6 

Kansas.   Contracts  such  as  these  are  routine  in  our  industry.  They  are  necessary  to  gain 

access  to  clinical  research  findings,  data  and  analyses. 

From  the  available  records,  Zeneca  paid  Dr.  Bernard  Fisher  and  Dr.  Carol  Redmond, 
about  $11,000  over  neaiiy  twenty  years  to  participate  in  educational  programs  and  to  appear 
before  the  FDA  in  support  of  our  drug  applications  and  filings.  These  activities  are 
consistent  with  the  accq)ted  practices  in  our  industry. 

Over  this  same  period  of  time,  NSABP  solicited  funding  from  Zeneca  and  several 
other  companies  to  help  support  NSABP  meetings.   According  to  available  records,  Zeneca's 
contributions  towards  these  activities  from  1976  through  1993  total  approximately  $585,000. 

The  purpose  of  the  NSABP  meetings  was  and  is  to  bring  NSABP  cooperative 
researchers  and  others  in  the  cancer  research  community  together  to  share  the  latest 
information  concerning  cancer  research.   NSABP  meetings  were  intense  working  sessions 
which  covered  topics  related  to  the  day  to  day  problems  and  situations  inherent  in  the 
running  of,  or  the  recruitment  for,  large  clinical  trials.   NSABP  controlled  the  agenda  for 
their  meetings  and  Zeneca  had  no  influence  over  the  scientific  program.   Continuing 
education  credit  was  often  available  for  attendance  at  these  meetings. 

Industry  funding  for  dinners  and  receptions  is  a  common  and  long  accq)ted  practice 
within  this  country's  scientific  community.   Zeneca's  conduct  was  entirely  consistent  with 
both  the  letter  and  spirit  of  FDA  policy  and  the  codes  of  conduct  adopted  by  the  American 
Medical  Association  (AMA)  and  the  Pharmaceutical  Research  and  Manufacturers  Association 
(PhRMA),  not  to  mention  our  own  stringent  internal  corporate  guidelines  as  they  applied 
then  and  now. 


117 


7 
Finally,  in  1988  at  the  request  of  the  University  of  Pittsburgh,  Zeneca  agreed  to 

participate  in  the  funding  of  a  research  chair  at  the  University.  The  purpose  of  this  chair 

was  to  assist  the  University  of  Pittsburgh's  Dqiartment  of  Surgery  in  their  stated  desire  to 

attract  and  recruit  graduate  students  and  faculty  members  interested  in  pursuing  researdi  in 

oncology  in  honor  of  Dr.  Fisher.   Zeneca  has  donated  $600,000  to  help  establish  the  chair. 

It  is  our  understanding  diat  sufficient  funds  have  y^  to  be  raised  to  complete  the  $1.S  million 

endowment  and  the  chair  has  not  been  created  or  filled. 

We  believe  that  our  financial  assistance  to  the  University  of  Pittsburgh  and  NSABP 
contributed  to  breast  cancer  research  in  the  U.S.  and  fostered  a  better  understanding  of  breast 
cancer  treatment  around  the  world.   We  do  not  believe  that  this  financial  support  caused 
NSABP  to  be  less  diligent  in  rqwrting  safety  information  regarding  tamoxifen.   In  fact, 
much  of  our  financial  support  was  given  specifically  to  obtain  extra  safety  rq>orts  to  submit 
to  the  FDA  and  to  facilitate  the  exchange  of  information  among  breast  cancer  researchers. 

In  conclusion,  we  at  Zeneca  are  committed  to  the  development  and  support  of  safe 
medicines  backed  by  good  science  and  proper  scientific  practices.  We  believe  tamoxifen  is  a 
safe  and  effective  medicine  vital  to  the  treatment  of  breast  cancer.  We  dq)Iorc  fraud  and 
poor  scientific  practices  in  clinical  research.   We  accordingly  are  pleased  to  assist  the 
Subcommittee  in  this  investigation. 

My  colleagues  and  I  would  be  happy  to  answer  any  of  your  questions. 


118 

Mr.  DiNGELL.  Thank  you,  Dr.  Patterson. 

Dr.  Plourde. 

Mr.  Plourde.  I  do  not  have  a  prepared  opening  statement,  Mr. 
Chairman. 

Mr.  DiNGELL.  We  would  be  glad  to  recognize  you  for  any  com- 
ments you  might  like  to  make  at  this  time. 

Mr.  Plourde.  No,  I  think  Dr.  Patterson  adequately  reflected  our 
comments. 

Mr.  DiNGELL.  Very  well. 

Mr.  Milbauer. 

Mr.  Milbauer.  Mr.  Chairman,  I  don't  have  a  prepared  state- 
ment, either.  I  am  just  here  to  help  answer  questions  that  the  com- 
mittee may  have. 

Mr.  DiNGELL.  Very  well,  gentlemen.  Thank  you  for  your  prepared 
statement. 

The  Chair  recognizes  the  distinguished  gentleman  from  Colorado 
for  questions. 

Mr.  SCHAEFER.  Thank  you,  Mr.  Chairman. 

Dr.  Patterson,  before  we  begin,  I  would  like  to  give  you  an  oppor- 
tunity to  allay  the  fears  of  some  of  the  general  public.  Is  tamoxifen 
effective  in  treating  women  with  breast  cancer? 

Mr.  Patterson.  There  is  a  very  simple  answer  to  that.  Yes,  sir, 
it  is  effective  both  in  the  advanced  disease — and  data  on  that  has 
been  generated  over  many  years  in  many  countries  in  the  world — 
it  is  effective  in  treating  the  early  disease  as  a  so-called  adjuvant 
therapy. 

Those  adjuvant  therapy  studies  have  been  conducted  also  in 
many  parts  of  the  world.  For  instance,  the  NSABP  data  only  rep- 
resents approximately  10  percent  of  the  major  studies  that  have 
been  conducted  worldwide  on  adjuvant  therapy  of  this  stripe.  Even 
if  you  were  to  remove  all  of  the  NSABP  studies  from  the  world 
overview  of  adjuvant  therapy,  the  conclusions  on  efficacy  and  safety 
would  remain  the  same. 

Mr.  SCHAEFER.  How  many  studies  have  been  conducted?  Are  we 
talking  about  a  large  number,  small  number?  How  many  women 
have  been  involved? 

Mr.  Patterson.  There  are  many  hundreds  of  trials  of  this  study 
throughout  the  world.  In  adjuvant  therapy,  for  instance,  there  are 
approximately  40  major  studies  worldwide;  but  in  the  advanced 
disease  and  in  other  treatments,  many  hundreds. 

Mr.  SCHAEFER.  Well,  the  news  reports  have  been  focusing  not  on 
the  treatment  trials  but  on  the  prevention  trials;  is  that  correct? 

Mr.  Patterson.  That  appears  to  be  the  case,  sir. 

Mr.  Schaefer.  That  appears  to  be  the  case? 

Mr.  Patterson.  The  safety  of  tamoxifen  for  prevention  has  been 
the  subject  of  much  media  discussion  in  this  country. 

Mr.  Schaefer.  I  understand  that — if  I  do  understand  it  correctly, 
prevention  trials  involved  giving  tamoxifen  to  women  with  a  high 
risk  of  getting  breast  cancer,  but  who,  in  fact,  have  not  really  con- 
tracted the  disease;  is  this  correct? 

Mr.  Patterson.  That  is  correct.  They  simply  do  not  have  the  dis- 
ease. 

Mr.  Schaefer.  You  indicated  in  your  opening  statement  that 
your  company  was  asked  to  participate  in  prevention  trials,  but  you 


119 

were  reluctant  to  do  so.  I  know  that  you  covered  this  somewhat 
briefly  in  your  opening  statement,  but  I  would  like  to  give  you  an 
opportunity  to  expand  on  your  answer. 

Why  was  it  that  you  were  reluctant  to  participate  in  these  pre- 
vention trials? 

Mr.  Patterson.  When  these  were  first  mooted  in  1985,  we  had 
concerns  on  a  number  of  fronts,  shared  also  by  a  number  of  sci- 
entists in  the  field.  The  drug  had  been  developed  as  a  medicine  for 
cancer.  Most  of  the  studies  had  been  in  women  with  the  advanced 
disease  and  had  not  been  long  term.  It  is  not  possible  to  do,  for  in- 
stance, placebo-controlled  studies  in  advanced  cancer,  so  the  abso- 
lute profile  of  this  agent  was  not  absolutely  clear;  and  whilst  the 
animal  toxicology  was  adequate  for  use  as  an  anticancer  agent,  it 
certainly  wasn't  adequate  for  use  in  patients  without  cancer.  So 
over  the  period  1985  to  1990,  studies  were  done  by  the  company. 

Also,  clinical  studies  were  done,  including  studies  by  NSABP, 
where  data  on  all  of  these  subjects  matured.  By  1990,  there  were 
data  on  controlled  studies  on  women  treated  for  long  periods  of 
time  with  the  drug,  who  had  not  got  advanced  disease,  and  there- 
fore the  side-effect  profile  could  be  recognized  more  clearly. 

We  had  further  animal  toxicology  which  had  included  some  very 
serious  findings  in  the  rat  liver,  which  were  a  concern  to  us  and 
to  the  outside  world.  And  we  also  had  a  whole  series,  or  a  whole 
increased  amount  of  safety  information  from  large  numbers  of  pa- 
tients; and  my  company,  in  reviewing  this  situation,  was  concerned 
that  although  women  at  high  risk  of  developing  breast  cancer  clear- 
ly have  a  major  worry  as  to  whether  they  are  going  to  develop  the 
disease,  and  anything  that  one  can  do  to  help  them  has  to  be  con- 
sidered, that  50  percent  of  the  women  who  develop  breast  cancer 
do  not  come  from  that  group;  and  that  even  when  a  woman  is  at 
high  risk  of  developing  breast  cancer,  a  relatively  small  number  of 
those  women  will  develop  the  cancer  over  a  relatively  short  period 
of  time. 

And  that  meant  that  for  the  majority  of  the  women  taking  part 
in  such  studies,  all  they  could  expect  to  get  from  a  medicine  such 
as  tamoxifen  was  the  side  effects  of  this  agent.  It  was  unlikely  to 
be  protecting  them,  although  there  were  some  suggestions  and 
there  are  some  suggestions  that  it  may  prevent  postmenopausal 
bone  loss  and  it  may  also  prevent  cardiovascular  diseases  that  re- 
sult from  the  effects  of  cholesterol. 

So  it  was  a  very  difficult,  risk-balanced  equation;  and  that  is 
clearly  why  it  is  being  debated  so  hard  in  public. 

Mr.  SCHAEFER.  But  you  were  asked  by  the  medical  community, 
I  think,  to  participate  in  these  prevention  trials;  were  you  not? 

Mr.  Patterson.  We  were. 

Mr.  Schaefer.  And  you  have  given  your  answer.  The  NCI  made 
this  request  as  well,  didn't  they? 

Mr.  Patterson.  NCI  did  make  this  request,  made  a  request  for 
the  material  for  the  trials. 

Mr.  Schaefer.  Given  your  consent,  you  made  it  conditional, 
upon  reviewing  the  consent  form,  that  it  was  to  be  given  to  women 
to  participate  in  the  trial;  is  that  correct? 

Mr.  Patterson.  That  is  correct. 


120 

Mr.  SCHAEFER.  Some  of  these  questions  lead  up  to  what  I  am 
going  to  be  asking  of  witnesses  in  the  future  here.  Did  you,  in  fact, 
review  the  consent  forms? 

Mr.  Patterson.  We  reviewed  a  model  consent  form  in  the  fall  of 
1991,  extensively  within  the  company. 

Mr.  SCHAEFER.  This  was  the  form  used  in  the  trials,  or  was  it 
changed  without  your  knowledge  and  consent? 

Mr.  Patterson.  The  consent  form  appears  to  have  evolved  con- 
siderably over  a  period  of  time  subsequent  to  this.  This  was  the 
consent  that  was  initially  submitted,  as  I  understand  it,  to  the 
FDA  by  NSABP;  and  there  were  changes  that  occurred  subsequent 
to  that,  which  we  did  not  review. 

Mr.  Schaefer.  OK,  so  there  were  changes. 

So  you  were  basically  unaware  of  the  affirmative  statement  con- 
cerning uterine  deaths  that  was  at  some  point  included  in  this  con- 
sent form? 

Mr.  Patterson.  We  did  not  rereview  the  consent  form  and  find 
that  statement. 

Mr.  Plourde.  Congressman,  if  I  can  add  a  statement  to  that 

Mr.  SCHAEFER.  Please. 

Mr.  Plourde.  Although  we  were  not  aware  that  this  change  had 
been  made  early  on,  I  believe  we  did  become  aware  toward  the 
middle  of  1993  that  this  change  had  been  made.  However,  at  the 
time,  we  were  told  by  the  NSABP  that  indeed  that  was  a  correct 
and  true  statement. 

Mr.  Schaefer.  Did  you  register  any  objection  to  this? 

Mr.  Plourde.  We  did  not. 

Mr.  Schaefer.  Was  it  a  true  statement? 

Mr.  Plourde.  We  were  told  it  was  a  true  statement  at  the  time 
that  we  became  aware  that  this  was  in  the  consent  form,  by  the 
NSABP. 

Mr.  Schaefer.  But  is  it  a  true  statement,  to  your  knowledge,  at 
this  point? 

Mr.  Plourde.  No,  it  is  not. 

Mr.  Schaefer.  Let  me  turn  to  the  issue  of  deaths  arising  from 
the  trials. 

You  requested  notification  of  any  deaths;  is  that  correct? 

Mr.  Patterson.  That  is  correct. 

Mr.  Schaefer.  You  were  notified  of  all  the  deaths? 

Mr.  Patterson.  We  were  notified  of  all  the  deaths,  yes. 

Mr.  Schaefer.  Approximately  how  many  death  notifications  do 
you  routinely  receive  in  the  course  of  a  year? 

Mr.  Patterson.  Over  the  course  of  a  year,  over  100  patients  are 
dying  across  the  NSABP  studies  involving  tamoxifen.  We  receive 
an  annual  printout  or  an  annual  computer  diskette  which  contains 
data  on  large  numbers  of  patients.  The  latest  one  contained  more 
than  300  patients. 

Mr.  Schaefer.  When  the  deaths  are  reported  to  you,  is  the  cause 
of  a  particular  death  indicated? 

Mr.  Patterson.  Deaths  are  reported  to  us  in  a  number  of  dif- 
ferent ways. 

Again,  perhaps  just  for  clarification,  women  are  expected  to  die 
in  these  studies.  They  are  suffering  from  breast  cancer.  Death  is 
not  always  an  unexpected  event,  so  deaths  were  reported  to  us  as 


121 

routine  or  deaths  were  reported  to  us  as  a  serious  or  unusual  event 
or  one  that  occurred  on  treatment;  and  there  is  a  difference. 

Mr.  SCHAEFER.  So  was  the  cause  reported  to  you? 

Mr.  Patterson.  Causality  was  not  linked  to  death,  although — I 
am  not  trying  to  be  difficult  in  answering  your  question.  The  way 
that  the  data  were  reported  to  us  was  that  other  factors  associated 
with  the  death  were  listed  in  a  separate  column,  but  causality  spe- 
cifically was  not  reported. 

Mr.  SCHAEFER.  Mr.  Chairman,  I  see  my  light  is  on,  and  I  will 
pass. 

Mr.  DiNGELL.  The  time  of  the  gentleman  has  expired. 

The  Chair  recognizes  now  the  gentleman  from  Ohio,  Mr.  Brown. 

Mr.  Brown.  Thank  you,  Mr.  Chairman.  I  would  like  to  follow  up 
on  some  of  Mr.  Schaefer's  questions  about  tamoxifen  and  some  of 
the — both  the  prevention — particularly  the  prevention  trials. 

Dr.  Patterson,  based  on  what  you  said,  I  would  infer  that  it  is 
very  important  for  Zeneca  to  be  kept  informed  in  a  timely  way  of 
information  regarding  side  effects  being  generated  in  Dr.  Fisher's 
breast  cancer  treatment  trials,  correct? 

Mr.  Patterson.  That  is  correct. 

Mr.  Brown.  How  and  when  did  your  company  convey  to  Dr. 
Fisher,  other  officials  in  NSABP,  the  importance  of  timely  and  ac- 
curate information  regarding  any  side  effects  of  tamoxifen? 

Mr.  Patterson.  Over  the  course  of  the  more  than  14  years  in 
which  we  were  associated  with  studies  that  they  were  conducting, 
my  company  on  many  occasions  interacted  with  Dr.  Fisher  and 
NSABP  on  the  issue  of  side  effects.  We  discussed  these  about  them, 
we  wrote  memos  to  them,  we  had  an  agreement  with  them,  the 
most  recent  of  which  was  in  1986,  on  exactly  what  side  effects  data 
would  be  reported  to  us  and  when. 

Mr.  Brown.  One  of  the  key  side  effects  that  Zeneca  was  con- 
cerned about  was  endometrial  cancers,  correct? 

Mr.  Patterson.  Correct. 

Mr.  Brown.  When  were  you  first  notified  that  at  least  one  uter- 
ine cancer  death  had  occurred  with  the  cause  attributed  to 
tamoxifen? 

Mr.  Plourde.  Mr.  Congressman,  maybe  I  can  try  to  answer  that. 

As  part  of  our  annual  obligation  to  report  adverse  events  to  the 
FDA,  we  requested  a  number  of  items  from  the  NSABP;  and  on  a 
yearly  basis  we  got  the  following  information: 

We  asked  them  to  provide  us  with  a  listing  of  deaths  or  with- 
drawals occurring  while  on  treatment  in  those  various  trials  that 
we  held.  In  addition,  we  asked  for  a  computer  diskette  on  second 
tumors,  and  those  tumors  are  malignancies  that  occur  after  the  di- 
agnosis of  breast  cancer.  In  addition,  we  also  take  information  ob- 
tained from  the  NSABP  annual  report  to  its  membership,  which 
contains  adverse  effects,  contains  narratives  on  serious  adverse  re- 
actions, and  it  contains  information  on  overall  survival. 

In  February  of  1992,  we  received  information  on  a  death  in  a  pa- 
tient who  had  the  diagnosis  of  endometrial  cancer.  We  requested 
further  information  from  the  NSABP  in  regards  to  this  patient,  and 
I  reviewed  that  information  and  assessed  the  death  to  be  attrib- 
utable to  endometrial  cancer.  However,  one  must  keep  in  mind  that 


122 

the  cause  of  death  is  often  very  difficult  to  establish  and  involves 
some  medical  judgment. 

I  did  have  a  discussion  with  the  NSABP  in  regards  to  this  death, 
and  it  was  their  belief  that  this  patient  had  died  from  other  causes, 
other  than  endometrial  cancer.  Hence,  I  reported  to  the  FDA  the 
information  that  I  received,  which  included  the  possible  relation- 
ship to  endometrial  cancer  as  well  as  to  pulmonary  embolus. 

As  Dr.  Patterson  mentioned  in  his  opening  statement,  most  re- 
cently we  were  informed  that  we  allegedly  had  information  on  a 
second  endometrial  cancer  death  in  February  of  1993,  and  that  was 
included  in  the  computer  diskette.  The  diskette  information  not 
only  includes  the  second  tumor  data  that  occurred  in  that  particu- 
lar trial,  but  also  the  survival  status  of  the  patient  at  the  time  of 
the  report.  There  is  no  causality  mentioned  in  that  particular  re- 
port, and  it  was  not  possible  at  that  time,  neither  is  it  possible  now 
that — in  reviewing  that  data  to  really  make  an  association  between 
endometrial  cancer  and  the  death  of  this  particular  patient. 

We  were  dependent  on  the  NSABP  to  medically  review  this  infor- 
mation and  to  provide  us  with  this  data,  so  the  first  time,  given 
the  scenario  that  I  have  just  stated,  that  Zeneca  appreciated  the 
deaths  had  occurred  related  to  endometrial  cancer  was  actually  in 
December  of  1993. 

Mr.  Brown.  So  you  are  saying  that  the  December  1993  case  was 
where  you  were  notified  by  NSABP  that  tamoxifen  was  the  cause 
of  the  uterine  cancer  specifically,  precisely? 

Mr.  Plourde.  No,  I  think  in  December  of  1993  we  were  informed 
that  the  patient's  death  had  been  attributable  to  the  endometrial 
cancer  in  a  patient  taking  tamoxifen. 

Mr.  Brown.  How  were  you  informed  of  that? 

Mr.  Plourde.  I  was  called  by  a  member  of  the  NCI  and  informed 
that  there  had  been  a  death  reported  at  the  NSABP  meeting. 

Mr.  Brown.  NSABP  did  not  call  you?  NSABP  said  it  at  a  meet- 
ing. Dr.  Fisher  said  it  at  a  meeting,  NCI  then  called  you?  You  have 
not  to  this  day  heard  it  directly  from  NSABP? 

Mr.  Patterson.  We  subsequently  have  had  information  from 
NSABP,  in  December,  listing  the  patients  who  have  died  and  giv- 
ing the  identifiers. 

Mr.  Brown.  What  triggered  that?  You  called  NSABP,  they  ac- 
knowledged that  was  the  case,  but  NSABP  never  initiated  the  call 
to  you  about  that  death  or  subsequent  deaths? 

Mr.  Plourde.  That  is  correct. 

Mr.  Brown.  Is  that  the  way  NSABP  should  be  operated? 

Mr.  Plourde.  No.  They  should  be  providing  that  information  to 
us  as  soon  as  it  is  known  to  them. 

Mr.  Brown.  Why  didn't  they  call  you?  What  is  your  view  of  why 
they  didn't  call  you? 

Mr.  Plourde.  It  is  difficult  to  speculate.  I  suspect  that  their  pri- 
orities in  regards  to  informing  us  were  different  than  ours,  but  I 
really  couldn't  say  why  they  didn't  call. 

Mr.  Brown.  It  is  not  like  they  didn't  notify  somebody  they  didn't 
know.  You  had  this  long-term,  dozen-plus  years  relationship  with 
them;  they  know  you,  you  know  them;  you  would  over  time  empha- 
size the  importance  of  that  two-way  exchange  of  information;  they 


123 

simply  failed  to  notify  a  very  important  colleague,  if  you  will,  of 
theirs? 

Mr.  Patterson.  It  is  conceivable  that  they  didn't  recognize  these 
as  endometrial  cancer  deaths  until  December  1993,  but  you  would 
have  to  ask  NSABP. 

Mr.  Brown.  Once  Zeneca  learned  of  these  deaths,  what  were 
your  responsibilities  and  whom  did  you  inform  as  your  duty  to  the 
public?  What  was  the  next  step  once  you  found  this  sort  of  indi- 
rectly through  NCI? 

Mr.  Patterson.  Our  step  is  to  inform  the  FDA  in  a  timely  fash- 
ion, and  as  necessary,  or  if  necessary,  to  alter  our  package  insert 
with  the  statement  then  that  is  read  by  all  doctors  using  the  drug. 

Mr.  Brown.  Did  the  information  about  the  deaths  necessitate 
any  changes  in  the  consent  form  for  either  the  prevention  studies 
or  the  treatment  studies? 

Mr.  Patterson.  The  consent  form  for  the  prevention  studies  has 
been  changed  to  remove  the  statement  that  there  have  been  no 
deaths. 

Mr.  Dingell.  The  time  of  the  gentleman  has  expired. 

The  gentlewoman  from  Pennsylvania. 

Ms.  Margolies-Mezvinsky.  Clarify  something  for  me.  From 
what  we  understand,  the  NSABP  presented  the  information  in  Oc- 
tober at  a  conference.  Tell  me  where  the  time  lapse  is. 

Mr.  Plourde.  There  was  an  annual  NSABP  meeting  in  October 
of  1993  where  the  endometrial  cancer  data  was  presented.  I  was 
in  attendance  of  that  meeting.  However,  a  lot  of  information  was 
being  conveyed;  there  were  two  projectors  going  on  simultaneously. 

And  I  was  taking  copious  notes,  and  I  did  not  note  at  that  par- 
ticular time  that  this  particular  death  had  apparently  been  men- 
tioned in  the  presentation;  and  this  was  duly  noted  by  a  member 
of  the  NCI. 

Ms.  Margolies-Mezvinsky.  So  in  other  words,  what  happened 
was  that,  at  some  point,  the  information  had  not  been  thoroughly 
gone  through,  and  it  fell  through  the  cracks? 

Mr.  Patterson.  Can  I  answer  that,  Congresswoman? 

It  would  be  very  unusual  for  any  group  to  report  a  death  to  us 
or  to  any  other  person  by  means  of  standing  up  in  a  public  meeting 
or  trial — a  meeting  such  as  that  one. 

Furthermore,  unless  that  patient's  trial  number  were  given,  we 
couldn't  identify  that  patient  and  deal  with  it  appropriately,  so  we 
would  expect  to  be  notified  in  writing  or  by  a  telephone  call  di- 
rectly, not  to  just  happen  to  be  sitting  in  a  meeting  where  some- 
thing like  that  is  presented. 

Ms.  Margolies-Mezvinsky.  Do  you  know  why  you  were  not  noti- 
fied? 

Mr.  Patterson.  No,  I  don't. 

Ms.  Margolies-Mezvinsky.  Dr.  Patterson,  once  Zeneca  had 
learned  of  these  deaths,  what  was  your  responsibility  and  whom 
did  you  inform — did  you  turn  to  with  regard  to  these  deaths? 

Mr.  Patterson.  The  first  responsibility,  as  a  pharmaceutical 
company,  is  to  notify  the  Food  and  Drug  Administration;  and  we 
did  that  in  early  January  of  1994. 

The  second  responsibility  is  to  inform  doctors  or  patients  associ- 
ated with  use  of  the  drug  of  that  occurrence  if  it  is  germane  to 


124 

their  treatment.  In  patients  who  are  treated  with  tamoxifen  for 
breast  cancer,  we  had  recognized  since  1989  that  endometrial  can- 
cer, uterine  cancer  was  occurring;  and  it  is  recognized  that  15  to 
20  percent  of  women  who  develop  endometrial  cancer  will  die  of 
that  disease,  as  I  said  in  my  opening  statement,  so  some  deaths 
were  not  unexpected. 

The  issue  really  relates  here  to  how  use  of  the  drug  for  breast 
cancer  can  be  translated  across  into  a  prevention  situation  where 
the  odds  of  death  are  significantly  different. 

Ms.  Margolies-Mezvinsky.  What  about  labeling?  Did  it  have 
any  effect  on  labeling? 

Mr.  Patterson.  The  labeling  was  changed  in  April  of  this  year 
to  include  the  statement — on  the  fact  that  there  has  been  a  death. 

Ms.  Margolies-Mezvinsky.  Did  the  information  about  the 
deaths  necessitate  any  changes  to  the  consent  forms  for  either  the 
prevention  or  the  treatment  studies? 

Mr.  Patterson.  It  clearly  had  an  effect  on  the  prevention  con- 
sent form,  and  I  believe  that  has  been  changed.  In  the  studies  of 
more  advanced  breast  cancer,  statements  have  been  in  the  consent 
for  a  number  of  years  stating  that  uterine  cancer  was  a  potential 
risk  of  taking  tamoxifen;  and  it  has  usually  been  included  in  the 
potentially  fatal  toxicity  section  of  the  protocol. 

I  don't  believe  there  were  any  statements  in  most  of  those  con- 
sent forms — although  Dr.  Plourde  may  want  to  add  to  this — about 
the  fact  that  there  had  been  no  deaths,  and  some  deaths  would  re- 
grettably be  expected. 

Ms.  Margolies-Mezvinsky.  In  determining  the  then  existing 
consent  form  needed  to  be  changed,  were  you  surprised  at  all  to 
learn  that  the  contents  of  the  consent  form  were  what  they  were? 

Mr.  Patterson.  Yes. 

Ms.  Margolies-Mezvinsky.  Could  you  elaborate,  please? 

Mr.  Patterson.  Although  we  had  reviewed  a  consent  form  in  the 
fall  of  1991,  that  had  not  contained  a  statement  that  there  had 
been  no  deaths.  That  statement  had  been  introduced  subsequently, 
and  we  had  not  reviewed  subsequent  consents.  Those  consents  had 
been  sent  to  the  company,  but  with  covering  letters  detailing  the 
changes  to  both  protocol  and  consent;  and  there  was  no — our  atten- 
tion was  not  drawn  to  that  fact,  so  it  was  not — it  was  a  surprise 
to  us  that  there  was  a  problem  in  this  area. 

Ms.  Margolies-Mezvinsky.  Do  you  know  who  added  the  state- 
ment? 

Mr.  Patterson.  I  do  not  know. 

Ms.  Margolies-Mezvinsky.  What  about  the  existing  consent 
form  for  the  prevention  study,  what  about  it  stood  out  to  you? 

Mr.  Patterson.  I  don't  think  I  understand  your  question. 

Ms.  Margolies-Mezvinsky.  What  about  the  existing  consent 
form  for  the  prevention  study  stood  out? 

Mr.  Patterson.  The  one  that  exists  today? 

Ms.  Margolies-Mezvinsky.  Yes. 

No,  the  one  that  existed  then. 

Mr.  Patterson.  At  the  time,  when  the  company  reviewed  it,  the 
company  felt  that  from  its  knowledge  of  the  toxicity  of  tamoxifen, 
it  was  quite  a  good  consent  form;  but  there  were  a  number  of 
things  that  were  in  our  package  insert  that  were  not  fully  covered 


125 

in  that  consent,  and  Dr.  Plourde  wrote  to  NSABP  informing  of  that 
at  the  time  that  we  reviewed  it. 

Ms.  Margolies-Mezvinsky.  The  consent  form  used  at  that  time 
had  a  statement  in  it  that  no  endometrial  cancer  deaths  had  been 
reported  due  to  the  use  of  tamoxifen,  correct? 

Mr.  Patterson.  At  the  time  the  study  was  initiated  in  June 
1992,  my  understanding  is,  yes,  that  statement  was  in  there. 

Ms.  Margolies-Mezvinsky.  Was  that  statement  in  the  original 
version  of  the  consent  form  for  the  prevention  study? 

Mr.  Patterson.  I  am  sorry,  I  didn't  hear  you. 

Ms.  Margolies-Mezvinsky.  Was  that  statement  in  the  original 
version  of  the  consent  form  for  the  prevention  study? 

Mr.  Patterson.  The  one  that  we  reviewed,  it  was  not  in  it. 

Ms.  Margolies-Mezvinsky.  Thank  you  very  much. 

Mr.  DiNGELL.  The  time  of  the  gentlewoman  has  expired. 

The  Chair  now  recognizes  the  gentleman  from  California,  Mr. 
Moorhead. 

Mr.  Moorhead.  Thank  you,  Mr.  Chairman. 

Did  approximately  the  same  number  of  women  take  the  placebo 
that  did  the  tamoxifen? 

Mr.  Patterson.  Which  study  are  you  referring  to,  Congressman? 

Mr.  Moorhead.  The  study  that  you  have  been  referring  to. 

Mr.  Patterson.  The  Study  B-14? 

Mr.  Moorhead.  Yes. 

Mr.  Patterson.  Yes,  that  is  correct. 

Mr.  Moorhead.  Have  any  of  the  women  who  took  the  placebo 
come  down  with  uterine  cancer? 

Mr.  Patterson.  There  have  not  been  any  deaths  from  uterine 
cancer  in  those  patients,  to  our  knowledge. 

Mr.  Moorhead.  What  percent  of  the  women  that  took  the 
tamoxifen  have  come  down  with  uterine  cancer?  How  many  have 
taken  it  and  how  many  came  down  with  the  illness? 

Mr.  Patterson.  It  is  about  25  out  of  1,400  are  the  numbers  that 
come  to  my  mind,  but  I  don't  have  those  numbers  in  my  head.  Con- 
gressman. 

Mr.  Moorhead.  Twenty-five  out  of  1,400.  Of  those  women  that 
took  the  placebo,  how  many  eventually  got  breast  cancer?  They 
were  people 

Mr.  Patterson.  Had  a  recurrence  of  their  disease? 

Mr.  Moorhead.  Yes. 

Mr.  Patterson.  Again,  sir,  I  don't  have  those  numbers. 

Mr.  Plourde.  Congressman,  maybe  I  can  provide  some  informa- 
tion on  that. 

Two  patients  in  the  B-14  trial- 


Mr.  Patterson.  Did  you  ask  of  breast  cancer  or 

Mr.  Moorhead.  What  I  am  trying  to  see  are  the  benefits  versus 
the  risks;  and  if  the  tamoxifen  patients  were  saved  from  cancer, 
from  breast  cancer  in  substantial  numbers,  I  want  to  see  whether 
the  risk  was  worthwhile.  Do  you  see  the  direction  I  am  going? 

Mr.  Patterson.  Yes,  I  do,  indeed. 

Mr.  Plourde.  Unfortunately,  all  of  the  adjuvant  breast  cancer 
studies,  when  they  were  initiated,  were  not  designed  to  provide  us 
with  information  on  endometrial  cancer.  When  this  was  determined 
in  follow-up,  this  was  investigated  quite  carefully.  Unfortunately, 


126 

due  to  the  various  biases  of  the  trial,  because  they  weren't  set  up 
in  proper  form,  it  is  difficult  to  assess  as  to  the  incidence  of  breast 
cancer  in  a  placebo  group.  In  fact,  the  two  patients  that  were  ran- 
domized to  placebo  in  the  B-14  trial  did  receive  tamoxifen  subse- 
quently and  had  breast  cancer. 

Mr.  Patterson.  Can  I  try  and  answer  your  question  for  you? 

There  are  less  women  who  developed  recurrent  breast  cancer  in 
the  placebo  group  than  in  the  treatment  group.  The  absolute  num- 
bers, I  don't  know  off  my  head,  but  about  Vs  less  developed  recur- 
rent breast  cancer  in  the  treatment  group  than  in  the  placebo 
group.  That  approximated — if  you  look  then  at  deaths,  where  there 
was  a  20  percent  reduction  compared  with  the — for  the  tamoxifen 
group  compared  to  the  placebo,  there  have  been  4  deaths  from 
endometrial  cancer.  We  are  talking  about  a  20-fold  difference  be- 
tween those  two  groups,  so  we  are  talking  about,  I  think,  80  deaths 
versus  4  deaths. 

Mr.  MOORHEAD.  I  would  think  those  figures  in  that  information 
would  be  something  that  was  very  important  to  give  to  women  that 
might  be  considering  using  the  drugs  so  that  they  could  weigh  the 
risks  one  way  or  the  other. 

Mr.  Patterson.  I  would  agree  with  you. 

Mr.  MoORHEAD.  Dr.  Patterson,  on  several  occasions.  Dr.  Fisher 
requested  funding  from  Zeneca.  Did  he  ever  ask  for  funding  for  im- 
proving his  administrative  staff? 

Mr.  Patterson.  Not  to  my  knowledge. 

Mr.  MoORHEAD.  But  did  he  ask  for  funding  for  receptions  at  the 
NSABP  meetings? 

Mr.  Patterson.  Yes,  he  did. 

Mr.  MOORHEAD.  Did  he  get  that? 

Mr.  Patterson.  Yes,  he  did. 

Mr.  MOORHEAD.  If  he  had  asked  for  funding  for  administrative 
staff,  do  you  think  he  would  have  gotten  it  from  you? 

Mr.  Patterson.  It  is  in  our  interests  and  everybody's  interests 
to  ensure  that  the  data  from  these  studies  are  as  good  as  they  can 
be;  and  I  am  sure  we  would  have  responded  positively  to  that  kind 
of  request. 

Mr.  MOORHEAD.  You  have  had  a  total  of  25  deaths  now  from 
uterine  cancer? 

Mr.  Patterson.  A  total  of  25  patients  have  developed  uterine 
cancer.  There  are  only  four  deaths. 

Mr.  MOORHEAD.  I  see.  Can  you  tell  whether  it  came  from  the — 
how  many  of  these  women  would  have  gotten  uterine  cancer 
whether  they  had  taken  tamoxifen  or  not? 

Mr.  Patterson.  That  is  a  difficult  question.  The  incidence  of 
uterine  cancer  as  a  background  in  the  population  is  one  way  that 
you  can  look  at  that,  but  the  control  group  is  the  other;  and  there 
are  actually  no  uterine  cancers  in  the  control  group  which,  in  itself, 
is  surprising.  You  would  have  expected  in  that  number  of  women 
of  that  age  group  over  that  period  of  time  to  have  had  some  of 
those  occur,  but  that  has  not  been  the  case. 

Mr.  Moorhead.  That  is  why  I  was  interested  in  knowing  how 
many  of  those  who  had  taken  the  placebo  had  eventually  come 
down  with  the  uterine  cancer.  I  think  that  would  be  something  that 


127 

would  help  you  understand  the  pluses  and  minuses  of  taking  the 
drug. 

Mr.  Patterson.  We  have  calculated  from  our  worldwide 
databases  how  the  incidence  of  endometrial  cancer  on  patients  tak- 
ing tamoxifen  varies  from  the  background  incidence  in  the  popu- 
lation at  large.  Patients  with  breast  cancer  do  have  an  increased 
incidence  of  uterine  cancer  anyway,  but  it  looks  to  us  as  if  the  in- 
crease associated  with  tamoxifen  is  somewhere  between  two-  and 
fivefold  over  the  background  incidence,  taking  all  of  the  studies  we 
are  aware  of  worldwide  together. 

Mr.  MOORHEAD.  I  guess  the  last  question — and  you  probably 
can't  answer  it — but  because  of  the  benefits  of  tamoxifen,  obviously 
not  liking  the  dangers  that  come  to  the  few  who  take  it,  is  it  pos- 
sible to  find  any  other  drug  or  any  change  in  tamoxifen  that  might 
eliminate  that  risk? 

Mr.  Patterson.  Yes,  it  is  possible  to  try  and  find  an  antiestrogen 
that  would  be  called  a  pure  antiestrogen,  that  is,  it  had  no  effects 
on  the  uterus  of  the  kind  that  we  are  describing;  and  that  has  been 
the  subject  of  research  in  my  company  and  a  number  of  others  for 
many  years.  It  is  possible  that  such  agents  will  be  developed  or 
even  that  a  partial  agonist  antiestrogen,  of  which  tamoxifen  is  one, 
that  didn't  have  those  particular  positive  effects  on  the  uterus 
might  also  be  possible  to  be  developed;  and  there  may  even  be  one 
or  two  in  very  early-stage  research  at  the  moment. 

Mr.  Moorhead.  You  are  dealing  with  a  subject  that  is  of  great 
concern  to  every  husband  in  the  world,  I  am  sure,  because  of  want- 
ing to  protect  their  wives,  and  when  things  like  this  come  up  you 
wonder  why  it  gets  members  of  the  committee  excited.  It  is  because 
they  are  concerned  for  their  loved  ones. 

mr.  Patterson.  It  touches  us  all.  Congressman. 

Mr.  Moorhead.  Thank  you,  Mr.  Chairman. 

Mr.  Brown  [presiding].  Thank  you,  Mr.  Moorhead. 

Dr.  Patterson,  returning  to  the  1993  time  period  that  both  I  and 
Mr.  Schaefer  earlier  had  asked  about,  the  subcommittee  obtained 
records  out  of  NSABP  depicting  a  slide  presentation  dated  in  Au- 
gust of  1993,  not  just  the  October,  and  we  talked  about  the  October 
seminar,  but  a  slide  presentation  August,  1993.  And  that  slide 
presentation  there  are  at  least  two  deaths  attributable  to — two 
deaths  that  were  attributed  from  that  cancer,  from  endometrial 
cancer,  in  the  B-14  study  with  patients  taking  tamoxifen. 

It  should  be  in  front  of  you.  One  is  numbered  006252,  where  a 
patient  died,  and  the  other  one  was  number  006254.  Were  you 
aware  of  this  information  in  August,  1993? 

Mr.  Patterson.  I  am  not  aware  that  any  member  of  the  com- 
pany received  that  slide  presentation  or  that  we  were  informed  of 
it  by  the  NSABP. 

Mr.  Brown.  Why  did  it  take  4  months?  We  know  that  was  pre- 
pared in  August.  We  are  not  saying  that  you  knew  about  it  in  Au- 
gust. We  know  it  was  prepared  in  August.  Why  did  it  take  that — 
take  4  months  from  the  time  these  slides  were  prepared  to  inform 
you,  as  the  manufacturer,  of  these  deaths? 

Mr.  Patterson.  That  is  a  question  you  must  ask  NSABP.  I  don't 
know  how  to  answer  that. 


128 

Mr.  Brown.  Isn't  it  true  that  by  the  summer  of  1993,  when  the 
information  was  being  prepared  for  these  slides,  if  they  were  actu- 
ally prepared  by  August  that  if  the  information  was  being  prepared 
in  the  summer  that  Zeneca  was  pressing  NSABP  regarding  any  in- 
cidence of  endometrial  cancers  associated  with  tamoxifen?  Were 
you  doing  that? 

Mr.  Patterson.  Yes.  We  had  been  conducting  worldwide  review 
of  this  particular  subject.  We  had  pressed  NSABP  very  hard  for 
their  up-to-date  information,  and  we  were  convening  a  panel  of  ex- 
perts to  help  us  to  review  the  situation  on  endometrial  cancer. 

Mr.  Brown.  So  you  don't  know  why  this  information,  then, 
wasn't  provided  to  you  as  you  were  holding  these  conversations 
with  them? 

Mr.  Patterson.  No,  we  don't  nor  why  it  wasn't  recognized  in 
their  consent  form  for  prevention. 

Mr.  Brown.  In  your  testimony  you  indicated  that  Zeneca  had 
provided  upwards  of  a  million  and  a  half  dollars  in  direct  support 
to  the  University  of  Pittsburgh  to  NSABP  for  a  variety  of  projects. 
Was  that  money  solicited  or  unsolicited?  Did  Zeneca  volunteer  it  or 
did  Pittsburgh  and  NSABP  request  it? 

Mr.  Patterson.  The  money,  which  was  paid  over  a  period  of 
some  20  years,  divides  into  several  different  categories,  some  of 
which  were  requested,  some  of  which  were  volunteered. 

For  moneys  for  data  handling  and  analyses  that  we  required  of 
them  to  allow  us  to  put  our  FDA  applications  in,  that  was  money 
that  we  offered  to  them  in  return  for  the  work  that  they  had  to  do 
over  and  above  their  normal  study  work  to  achieve  those  analyses. 

Mr.  Brown.  So  did  you  feel  obliged  to  provide  them  those  funds 
in  some  manner? 

Mr.  Patterson.  That  would  be  absolutely  normal  practice  for  us 
to  do  that,  yes. 

Mr.  Brown.  What  kind  of  benefits  did  you  enjoy  by  providing 
these  funds? 

Mr.  Patterson.  The  funds  for  the  data  handling  allowed  us  to 
provide  information  to  the  FDA  on  the  beneficial  effects  of 
tamoxifen  in  Studies  B-9  and  B-14  in  particular,  and  also  to  pro- 
vide, as  far  as  we  could,  a  risk-benefit  analysis  by  providing  side 
effects  and  adverse  reaction  information  on  those  studies  and  on  all 
other  tamoxifen  studies  conducted  by  NSABP. 

Mr.  Brown.  Did  you  know  that  some  of  that  money,  to  the  tune 
of  hundreds  of  thousands  of  dollars,  were  going  to  some  of  the  par- 
ties and  other  entertainment  that  Chairman  Dingell  mentioned? 

Mr.  Patterson.  That  was  by  separate  request,  so  the  data  for — 
the  data  handling  was  separately  requested  for  the  data 

Mr.  Brown.  Separately  requested  by  Dr.  Fisher  or  by  whom? 

Mr.  Patterson.  By  the  NSABP,  yes.  They  didn't  request  the 
money  for  the  data  handling.  We  requested  the  information  for 
which  we  offered  money  for  them  to  provide  us  with  that  scientific 
information.  The  money  for  the  receptions  at  the  NSABP  annual 
meetings  or  biannual  meetings  was  requested  of  us  by  NSABP  for 
that  specific  purpose. 

Mr.  Brown.  You  say  receptions.  Chairman  Dingell  made  it  look 
a  little  more  elaborate  than  receptions.  But  you  knew  that  money 
was  to  be  used  for  that  purpose? 


129 

Mr.  MiLBAUER.  Yes,  Congressman.  If  I  could  answer  that,  as  you 
know  or  as  perhaps  you  don't  know,  NSABP  would  hold  biannual 
and  then  it  became  annual  meetings  for  the  purpose  of  bringing  to- 
gether all  of  their  cooperative  researchers  to  be  able  to  discuss  over 
a  period  of  3  or  4  days  how  trials  ought  to  be  run,  what  new  proto- 
cols ought  to  be  considered,  discuss  the  analyses  of  information 
that  would  go  on.  And  these  were  heavy  scientific  sessions  that 
would  take  place  over  these  3  or  4  days. 

On  one  evening  they  would  hold — they  would  want  to  hold  a  so- 
cial event.  And  we  were  asked,  and  it  began  almost  18  years  ago, 
if  we  would  sponsor  such  an  event.  These  were  receptions.  These 
were  receptions  that  were  not  sit-down  dinners.  They  did  provide 
food,  hors  d'oeuvres,  if  you  will,  and  cocktails,  but  these  were — ^this 
was  an  integral  component  of  the  opportunity  for  these  researchers 
to  get  together  in  an  informal  session,  exchange  information. 

We  didn't  control  and  had  no  involvement  with  the  agenda  for 
such  meetings,  and  these  are  all  within  the  guidelines  that  are 
published  by  the  American  Medical  Association  with  respect  to 
making  sure  that  the  substantial  majority  of  the  time  devoted  to 
these  scientific  meetings  were  devoted  to  the  sessions  and  that  the 
expenses  were  modest  and  that  they  did  facilitate  exchange.  And 
within  the  spirit  of  that,  that  is  what  we  were  sponsoring  over 
these  many  years. 

Mr.  Brown.  Modest.  Two  things  come  to  mind  when  you  say  they 
were  modest,  and  you  continue  to  use  the  word  reception.  I  have 
not  been  to  a  lot  of  receptions  that  cost  in  the  rough  ballpark  of 
$50,000  to  $80,000,  which  several  of  these  cost.  And,  second,  these 
weren't  held  in  Pittsburgh.  They  were  held  in  Hilton  Head.  They 
were  held  in  the  Canadian  Rockies. 

I  am  not  disputing  your  right  as  a  private  corporation  to  do  that. 
I  am  just  questioning  your  labeling  of  some  of  these  as  educational, 
as  routine,  as  simple  receptions. 

Mr.  MiLBAUER.  Well,  Congressman,  let  me  address  that  for  you. 
It  is  common  practice  between  the  pharmaceutical  industry  and 
scientific  institutions  and  medical  institutions  to  sponsor  and  help 
in  the  conduct  of  those  meetings,  but  I  think  it  is  important  to  dis- 
tinguish. We  did  not  choose  the  venue  for  the  meetings.  The  venue, 
whether  it  was  in  Bal  Harbour  or  in  San  Francisco,  that  was  cho- 
sen by  the  NSABP.  We  had  no  role 

Mr.  Brown.  But  they  also  knew  they  had  a  sugar  daddy  to  help 
them  defray  the  expenses. 

Mr.  MiLBAUER.  The  only  expenses  we  believe  to  our  knowledge 
that  was  defrayed  in  terms  of  administrative  expenses,  because  it 
is  a  nonprofit  organization,  was  the  reception  that  evening.  Our 
funds,  to  the  best  of  our  knowledge,  were  not  utilized  in  the  accom- 
modations for  the  attendees  nor  for  the  transportation  to  those 
meetings. 

And,  in  fact,  I  think  it  also  was  important  when  you  look  at  a 
$50,000  or  an  $80,000  reception  is  that  the  numbers  of  attendees 
at  these  meetings  grew  over  the  years.  That  is,  there  were  only 
about  6  or  so  receptions  of  some  almost  30  that  were  in  that,  but 
the  number  of  attendees  approached  1,000  or  even  more  than  that 
on  some  occasions. 

Mr.  Brown.  I  would  yield  to  you,  Mr.  Schaefer. 


130 

Mr.  SCHAEFER.  Two  quick  questions.  Were  any  Federal  moneys 
involved  in  the  sponsoring  of  these  receptions? 

Mr.  MiLBAUER.  To  the  best  of  my  knowledge,  there  were  no  Fed- 
eral moneys  provided  for  the  reception.  In  fact 

Mr.  SCHAEFER.  How  about  transportation,  lodging,  et  cetera? 

Mr.  MiLBAUER.  I  don't  know.  It  would  be  whatever  NSABP  would 
fund.  They  may  have  gotten  that  from  NCI,  but  we  were  actually 
advised  by  the  NSABP  that  they  could  not  get  funding  from  the 
Federal  Government  for  the  reception.  And  it  was  on  that  basis — 
they  would  ask  other  companies  to  help  sponsor  the  meetings,  and 
this  was  the  way 

Mr.  SCHAEFER.  I  am  talking  about  the  reception  alone.  I  mean 
the  transportation  down,  the  lodging,  everything  else. 

Mr.  MiLBAUER.  To  the  best  of  my  knowledge,  there  was  no  Fed- 
eral funding  for  the  reception. 

Mr.  SCHAEFER.  For  the  reception  only.  All  right.  And  you  paid 
100  percent  of  the  reception? 

Mr.  MiLBAUER.  Yes.  We  would  pay  those  to  the  hotel  or  we  would 
pay  those  to  a  meeting  planner.  We  did  not  pay  those  moneys  to 
the  NSABP  or  anyone  else.  It  was  just  for  those  arrangements. 

Mr.  SCHAEFER.  All  right.  Well,  we  will  ask  questions  about  trans- 
portation and  lodging  later. 

Mr.  Brown.  I  would  add  that  the  transportation  to  these  places 
other  than  Pittsburgh  was  apparently  borne  by  the  Federal  Gov- 
ernment. 

One  further  question  about  this,  and  then  I  have  a  brief  set  of 
questions.  You  recently  dropped  your  contribution  to  NSABP  from 
the  $50,  $60,  $70,  $80,000  range  down  to  $10,000.  Yet  you  make 
these  statements  that  they  were  routine,  and  they  were  simply  re- 
ception. Why  did  you  drop  that  amount? 

Mr.  MiLBAUER.  I  believe  that  the  meeting  of  $10,000  was  a  sec- 
ond meeting  in  1993,  and  I  think  it  was  just — I  don't  recall  wheth- 
er the  request  was  for — in  fact,  I  don't  know  what  reception  took 
place  at  that  meeting,  but  we  just  funded  it  to  $10,000. 

The  prior  time  we  actually  just  provided  them  with  a  grant  be- 
cause during  that  time  it  was  unclear  as  to  whether  the  kinds  of 
sponsorship  of  these  meetings  would  be  within  the  guidelines  be- 
cause the  guidelines  were  evolving. 

Mr.  Brown.  So,  number  one,  what  was  the  amount  of  the  grant? 
Second,  are  you  going  back  up  to  the  $50,000  to  $80,000?  Is  the 
$10,000  just  a  temporary  drop  just  prior  to  this  hearing  and  then 
back  to  the  50,000,  80,000? 

Mr.  MiLBAUER.  The  $10,000  was  provided  in  1993. 
There  is  actually  a  meeting  that  is  taking  place  at  the  present 
time.  We  were  requested  to  provide  the  typical  sponsorship. 

We  received  a  request  earlier  this  year.  At  the  time,  we  deferred 
responding  to  that,  and  I  think,  despite  the  fact  that  we  think 
there  is  no  impropriety  at  all,  in  fact  we  have  reviewed  the  guide- 
lines. We  keep  looking  at  them  to  determine  that  they  are  within 
the  guidelines.  We  believe  they  are,  but  given  the  publicity  and 
given  the  fact  that  there  was  going  to  be  this  hearing  today,  we 
had  declined  in  providing  support  to  this  meeting,  and  in  fact 
NSABP's  response  to  that  is,  given  the  situation,  they  would  not 
want  to  put  themselves  into  a  position  of  receiving  moneys  for  that. 


131 

But  I  would  say  affirmatively  on  the  basis  of  what  the  guidelines 
and  how  they  operate,  we  see  nothing  wrong  with  what  we  have 
done  in  the  past. 

Mr.  Brown.  To  change  the  subject,  is  your  parent  company  ICI? 
Is  there  still  affiliation  with  ICI? 

Mr.  Patterson.  No,  we  are  now  a  separate  company.  Zeneca  is 
a  totally  separate  share  holding  company. 

Mr.  Brown.  When  was  ICI — when  was  the  disaffiliation,  if  you 

will? 

Mr.  Patterson.  In  1991.  I  am  sorry,  1993.  My  apologies. 

Mr.  Brown.  ICI  is  to  my  understanding,  if  you  can  help  me  with 
this,  the  manufacturer  of  DDT  and  a  distributor  of  DDT? 

Mr.  Patterson.  I  don't  think  that  I  can  answer  for  what  ICI 
does.  I  am  not  an  employee  of  ICI.  I  am  a  physician  working  in  a 
pharmaceutical  company. 

Mr.  Brown.  I  understand  that.  I  am  only  asking  if,  in  fact,  that 
is  the  case.  If  these  companies  were  affiliated,  I  would  think  that 
you  would  know  whether  or  not  ICI  manufactured  DDT. 

Mr.  MiLBAUER.  It  would  be  a  speculation  on  our  part,  but  I  be- 
lieve that  they  do  not  manufacture  DDT,  but  I  can't  say  with  any 
certainty  whether  ever  in  its  history  that  they  have. 

Mr.  Brown.  OK.  I  was  just  curious  because  the  information  that 
I  have  been  given  is  that  ICI  does,  in  fact,  manufacture  DDT  and 
that  I  find  it  curious  that  companies  that  are  affiliated — one  is 
doing  such  good  research  on  breast  cancer  as  you  have  done,  and 
if  you  are  not — if  you  have  no  knowledge  of  whether  it  manufac- 
tures DDT  and  whether  DDT— if  there  is  any  scientific  proof  of 
whether  DDT  actually  increases  the  risk  of  breast  cancer,  we  will 
drop  it  at  that. 

Mr.  MiLBAUER.  I  think  probably  the  best  thing — and  I  would 
agree  with  Dr.  Patterson — is  for  the  committee  to  receive  some  in- 
formation from  ICI  with  respect  to  whether  they  do  or  they  don't. 

Mr.  Brown.  Other  questions? 

Thank  you,  gentlemen 

I  am  sorry,  Mr.  Schaefer,  the  gentleman  from  Colorado. 

Mr.  Schaefer.  Two  quick  questions.  Then  I  want  to  jump  back 
to  this  1992  death.  After  you  made  the  determination  that  the 
death  resulted  from  uterine  cancer,  you  did  notify  the  FDA;  is  that 
correct? 

Mr.  Plourde.  That  is  correct. 

Mr.  Schaefer.  Did  you  notify  Dr.  Fisher? 

Mr.  Plourde.  I  don't  recall  if  I  spoke  to  Dr.  Fisher  or  to  his  as- 
sistant, Dr.  Wickerham. 

We  do  know — and  we  have  records  that  we  obtained  further  in- 
formation in  this  case  from  Dr.  Wickerham.  Upon  review  of  that  in- 
formation I  did  discuss  the  case  with  Dr.  Wickerham,  who  felt  that 
this  patient  had  actually  died  of  a  pulmonary  embolus  rather  than 
endometrial  cancer. 

However,  given  the  problems  in  accurately  interpreting  the  cause 
of  death,  I  reported  to  the  FDA  that  it  was  possible  that  this 
woman  had  died  from  endometrial  cancer,  contributed  by  pul- 
monary embolus. 

Mr.  Schaefer.  Let  me  get  this  straight.  You  said  that  you  don't 
recall  whether  or  not  you  notified  Dr.  Fisher. 


132 

Mr.  Plourde.  The  NSABP  was  notified,  but  Dr.  Fisher  himself, 
I  can't  say  for  certain  that  I  notified  him  personally  of  that. 

Mr.  SCHAEFER.  You  can't  remember  that? 

Mr.  Plourde.  I  can't  recall.  I  know  I  have  had  discussions  with 
the  NSABP,  Dr.  Wickerham,  in  this  matter. 

Mr.  SCHAEFER.  Should  the  NSABP  have  been  able  to  determine 
the  cause  of  this  patient's  death? 

Mr.  Patterson.  The  NSABP  had  access  to  the  full  case  record 
forms,  access  to  the  hospital  where  the  patient  died  and  was  treat- 
ed. We  only  had  access  to  a  one-paragraph  summary. 

Mr.  SCHAEFER.  I  understand  that.  I  am  asking  a  question, 
though.  The  NSABP — could  they  have  determined  the  cause  of  the 
death? 

Mr.  Patterson.  They  can  determine  the  cause  of  death.  They 
could  have  as  per  their  judgment,  but  cause  of  death  is  not  an  easy 
judgment  medically. 

Mr.  SCHAEFER.  Should  they  have  done  this? 

Mr.  Patterson.  With  a  retrospectroscope,  they  clearly  have  de- 
termined that  to  be  the  cause  of  death,  but  at  the  time  they  did 
not. 

Mr.  SCHAEFER.  They  did  not.  Thank  you. 

Mr.  Brown.  Thank  you,  Mr.  Schaefer. 

Gentlemen,  thank  you  for  your  testimony.  Appreciate  your  being 
here. 

The  Chair  will  now  call  up  the  second  panel:  Dr.  J.  Dennis  O'Con- 
nor, chancellor.  University  of  Pittsburgh;  Dr.  Ronald  Herberman, 
interim  chairman.  National  Surgical  Adjuvant  Breast  and  Bowel 
Project;  and  Dr.  Thomas  Detre,  senior  vice  chancellor  for  health 
sciences. 

Dr.  O'Connor,  Dr.  Detre,  Dr.  Herberman,  welcome.  In  front  of 
you  are  the  rules  of  the  subcommittee,  the  committee,  the  full  com- 
mittee, and  the  House  of  Representatives.  Feel  free  to  consult  these 
throughout. 

You  are  allowed  certainly  to  have  legal  counsel  here,  and  it  is  the 
tradition  of  this  committee  to  testify  under  oath,  if  you  would  raise 
your  right  hand. 

[Witnesses  sworn.] 

Mr.  Brown.  Please  be  seated. 

Dr.  O'Connor,  would  you  begin  with  your  opening  testimony, 
please? 

TESTIMONY  OF  J.  DENNIS  O'CONNOR,  CHANCELLOR,  UNIVER- 
SITY OF  PITTSBURGH,  ACCOMPANIED  BY  THOMAS  DETRE, 
SENIOR  VICE  CHANCELLOR  OF  HEALTH  SCIENCES,  AND 
RONALD  B.  HERBERMAN,  INTERIM  CHAIRMAN,  NATIONAL 
SURGICAL  ADJUVANT  BREAST  AND  BOWEL  PROJECT 

Mr.  O'Connor.  Thank  you,  sir. 

Mr.  Chairman  and  members  of  the  subcommittee,  I  am  Dennis 
O'Connor,  chancellor  of  the  University  of  Pittsburgh,  and  I  sin- 
cerely thank  you  for  accommodating  my  request  to  appear  here 
today.  I  asked  to  come  because  I  want  to  state  in  person  that,  as 
the  senior  executive  officer  of  the  University  of  Pittsburgh,  I  accept 
responsibility  for  the  past  administrative  deficiencies  of  the  Na- 
tional   Surgical    Adjuvant    Breast    and    Bowel    Project,    which    is 


133 

headquartered  at  our  university.  I  also  accept  and  welcome  the  re- 
sponsibility to  make  things  right. 

I  have  stated  these  commitments  to  Dr.  Broder,  the  Director  of 
the  National  Cancer  Institute,  as  well. 

I  deeply  regret  and  apologize  for  any  anxiety  induced  in  cancer 
patients  and  the  general  public  as  a  result  of  this  matter.  I  am  par- 
ticularly sensitive  to  this  unfortunate  outcome  because  my  wife  is 
an  oncology  nurse  who  specializes  in  helping  women  with  breast 
cancer  to  cope  with  the  stress  of  their  condition. 

As  my  colleagues,  Drs.  Detre  and  Herberman,  will  describe  to 
you,  a  large  team  consisting  of  many  of  the  University's  most  able 
people,  as  well  as  outside  experts,  have  been  working  diligently  to 
make  the  changes  that  we  believe  are  warranted  to  justify  restored 
public  confidence  in  us  and  to  advance  this  important  and  historic 
research. 

Mr.  Chairman,  as  you  know,  there  has  been  no  shortage  of  public 
comment  on  this  matter,  with  several  hundred  news  accounts  pub- 
lished and  broadcast  already.  The  media  commentary  is,  on  bal- 
ance, healthy,  for  it  heightens  public  awareness  of  the  issues  and 
the  awareness  of  the  University  faculty  and  administrators.  But  I 
do  want  to  identifv  two  points  that  some  of  the  news  accounts  may 
have  obscured  rather  than  clarified. 

While  it  is  gratifying  and  reassuring  that,  as  far  as  is  known, 
NSABP's  research  findings  continue  to  be  entirely  sound,  charges 
of  deficient  administration  are  not  adequately  answered  by  merely 
asserting  that  the  research  findings  remain  valid.  Falsified  data  is 
odious  under  any  condition. 

Second,  while  credit  for  the  intellectual  achievements  of  a  faculty 
member  goes  to  that  faculty  member,  the  university  is  ultirnately 
responsible  for  the  administration  of  research.  All  honor  that  is  due 
Dr.  Bernard  Fisher  and  his  colleagues  for  their  achievement  in  this 
path-breaking  breast  cancer  research  is  their  honor.  We  fully  recog- 
nize, however,  that  the  responsibility  for  competent  research  ad- 
ministration ultimately  rests  with  us  at  the  University. 

To  learn  and  to  teach  from  observation  and  experience  is  the 
central  mission  of  a  University  and  the  essence  of  science.  What 
are  some  of  the  lessons  we  can  learn  from  this  experience?  What 
can  we  now  teach  based  on  this  experience?  These  large  and  dif- 
ficult questions  are  being  considered  intensively.  I  am  not  yet 
ready  to  offer  a  complete  list  of  possible  answers,  but  I  am  ready 
to  suggest  several. 

First,  we  must  establish  better  mechanisms  to  ensure  that  even 
our  most  experienced,  tested  and  accomplished  faculty  are  respon- 
sive to  administrative  imperatives  as  well  as  to  their  pressing  and 
sometimes  compelling  intellectual  agendas. 

We  must  find  better  ways  to  promote  an  environment  in  which 
faculty  understand  that  the  University's  proper  oversight  in  areas 
of  administrative  compliance  neither  conflicts  with  academic  free- 
dom nor  collides  with  institutional  respect  for  faculty  members' 
judgment. 

Those  of  us  who  have  an  administrative  role  in  the  universities 
must  constantly  remind  ourselves  that  while  loyalty  to  colleagues 
is  important,  depending  on  the  facts  of  the  case,  accountability  to 
the  public  supersedes  that  relationship. 


134 

We  must  be  very  sensitive  to  the  importance  of  accurately  dis- 
closing in  a  timely  manner  emerging  research  developments  that 
carry  potential  to  affect  the  public  adversely,  even  where  there  may 
be  some  uncertainty  as  to  the  facts. 

We  must  elicit  from  research  sponsors  clear  statements  of  their 
needs  and  expectations.  When  we  receive  such  statements  from  re- 
search sponsors,  we  must  follow  the  statements  punctiliously.  If  we 
disagree  with  the  statements,  we  must  take  the  initiative  to 
achieve  a  meeting  of  the  minds.  If  the  statements  are  unclear,  we 
must  get  them  clarified.  Ambiguity  in  matters  of  administrative  re- 
sponsibility can  undermine  relations  with  research  sponsors  and 
indeed  disserve  the  public. 

The  role  of  this  subcommittee  and  its  staff  in  this  matter  re- 
quires special  note,  and  I  will  speak  candidly.  Mr.  Chairman,  as 
you  yourself  have  stated,  this  subcommittee  has  a  reputation  for 
sharp  teeth.  Few  relish  being  investigated  by  this  subcommittee. 
During  the  last  2  months  we  have  had  a  fairly  grueling  set  of  inter- 
actions, document  productions,  interviews  and  information  de- 
mands from  the  subcommittee  staff.  This  work  has  been  painstak- 
ing and  not  particularly  pleasurable. 

However,  I  also  wish  to  acknowledge  that  the  subcommittee  and 
its  staff,  once  the  facts  were  collected,  dissected  and  analyzed,  did 
not  shrink  from  working  very  constructively  with  the  National 
Cancer  Institute  and  the  University  to  get  the  NSABP  research 
back  on  track,  to  preserve  the  best  of  NSABP,  and  hopefully  enable 
us  to  improve  the  rest. 

If,  in  the  end,  the  approach  taken  by  this  subcommittee  had  been 
negative  and  destructive  rather  than  positive  and  constructive, 
breast  cancer  patients,  present  and  future,  would  have  been  sub- 
jected to  further  suffering.  Instead,  they  are  being  helped  because 
of  the  advancement  of  a  healthier  partnership  between  NSABP  and 
NCI  that  prevailed  before.  This  subcommittee  has  been  instrumen- 
tal in  that. 

We  are  learning  that  sharp  teeth  can  be  painful  and  embarrass- 
ing but,  unfortunately,  can  also  be  necessary  from  time  to  time. 

We  will  not  claim  today,  Mr.  Chairman,  to  know  with  mathe- 
matical precision  exactly  the  right  mix  of  breathing  room  and  over- 
sight that  is  required  at  a  University  to  produce  great  science,  to 
generate  medical  knowledge,  to  save  lives  and  alleviate  suffering. 
Toward  that  ideal  balance  we  strive  imperfectly.  Be  assured,  how- 
ever, that  the  knowledge  that  we  are  and  will  always  be  imperfect 
does  not  discourage  us.  This  episode  motivates  us  to  work  harder 
to  achieve  these  goals,  which  we  share  with  the  Federal  Govern- 
ment and  the  American  people. 

Thank  you,  sir. 

Mr.  DiNGELL.  Thank  you.  Dr.  O'Connor. 

Dr.  Detre. 

TESTIMONY  OF  THOMAS  DETRE 

Mr.  Detre.  Mr.  Chairman  and  members  of  the  subcommittee,  I 
am  Dr.  Thomas  Detre,  senior  vice  chancellor  for  Health  Sciences. 

Mr.  DiNGELL.  Doctor,  the  Chair  apologizes.  We  have  a  miserable 
public  address  system,  as  you  will  fmd. 

Mr.  Detre.  My  apologies.  Can  you  hear  me  now,  Mr.  Chairman? 


135 

I  am  here  in  response  to  your  invitation  to  comment  on  the 
NSABP  matter  and  to  answer  your  questions. 

Mr.  Chairman,  after  even  more  than  40  years  in  America,  I  still 
speak  with  an  accent.  When  I  came  to  the  United  States  several 
years  after  World  War  II,  physicians  like  myself  who  had  accents 
were  desperately  needed  because  of  the  shortage  of  skilled  sci- 
entists in  America's  University  hospitals  and  laboratories.  But  now 
I  am  happy  to  report  people  like  me  are  rather  obsolete  because 
today  there  are  so  many  exceptionally  able  American  scientists. 
Today,  most  of  the  time,  American  senior  faculty  train  foreign  stu- 
dents, as  well  as  American  students,  not  vice  versa.  That  is  the 
amazing  progress  of  American  science  in  our  lifetimes. 

During  the  same  period,  as  you  know,  along  with  spectacular  ad- 
vances in  biomedical  research  in  the  United  States,  the  science  of 
treatment  evaluation  also  progressed  rapidly.  The  multi-center 
clinical  trial,  of  which  NSABP  is  a  renowned  example,  is  univer- 
sally regarded  as  a  premier  approach  for  testing  medical 
hypotheses. 

Dr.  Bernard  Fisher  has  spent  his  lifetime  developing  such  trials 
to  gauge  the  efficacy  of  breast  cancer  treatments.  These  trials  nota- 
bly involved  his  historic  discovery  that  lumpectomy  followed  by  ra- 
diation is  fully  as  effective  as  the  more  devastating  and  disfiguring 
radical  mastectomy  which,  before  Dr.  Fisher's  discovery,  was  the 
treatment  of  choice  for  many  forms  of  breast  cancer. 

This  landmark  finding,  I  might  add,  has  since  been  confirmed 
independently  by  at  least  five  large-scale  clinical  trials  in  the  Unit- 
ed States  and  Europe. 

One  of  the  advantages  of  a  multi-center  clinical  trial  over  the 
usual  study  conducted  in  a  single  or  several  academic  medical  cen- 
ters is  that  the  multi-center  trial  can  test  a  very  large  number  of 
patients  in  diverse  geographical,  socioeconomical  and  medical  set- 
tings, making  the  results  more  readily  subject  to  generalizations 
about  the  population  at  large.  Biostatisticians  also  note  the  tend- 
ency of  such  large  studies  to  be  valid  by  reason  of  the  studies'  sta- 
tistical power. 

A  drawback  of  the  broad  scale  multi-center  clinical  trial,  how- 
ever, is  the  difficulty  in  controlling  the  quality  and  uniformity  of 
the  data  coming  from  numerous  investigators  in  numerous  centers, 
some  of  whom  are  not  highly  expert  in  conducting  such  research. 
This  difficulty  may  explain  some  of  the  current  issues  relating  to 
NSABP.  I  say  explain,  I  do  not  say  excuse. 

We  still  do  not  know  nor  does  the  National  Cancer  Institute, 
with  complete  and  total  thoroughness,  exactly  what  fraction  of  the 
NSABP  data  were  unreliable.  We  are  still  double  checking,  as  is 
NCI.  But  based  on  everything  we  know  to  date — and  it  is  exten- 
sive— and  despite  the  wide-ranging  questions  about  certain  NSABP 
administrative  practices,  that  no  knowledgeable  person  has  chal- 
lenged the  continuing  validity  of  the  scientific  conclusions. 

I  report  this  conclusion  to  the  subcommittee  not  to  minimize  con- 
cerns about  our  responsibility  to  administer  by  the  highest  stand- 
ards but  to  reassure  breast  cancer  patients  and  their  families,  as 
have  the  responsible  government  agencies,  that  public  health  and 
safety  are  not  compromised.  The  soundness  of  the  scientific  conclu- 
sions is  not  the  issue  before  us  today. 


136 

However,  in  retrospect,  I  believe  that  the  academic  community 
has  failed  to  arm  patients,  their  families  and  the  advocacy  groups 
with  sufficient  information  about  clinical  trials  to  protect  them 
from  the  overwhelming  anxiety  that  they  experienced  when  they 
were  confronted  with  the  news  that  some  data  in  these  trials  were 
flawed.  I  am  sure  that  in  collaboration  with  NIH  we  can  do  better. 

We  are  here  because,  notwithstanding  the  soundness  of  the  sci- 
entific conclusions,  the  quality  of  administration  of  NSABP  has 
been  questioned.  In  close  coordination  with  the  National  Cancer  In- 
stitute and  other  cognate  agencies,  we  at  the  University  have  been 
working  very,  very  intensively  to  identify,  analyze  and  respond  to 
each  of  these  concerns. 

For  example:  The  University  appointed  one  of  its  most  distin- 
guished senior  scientists,  Dr.  Ronald  Herberman,  to  be  interim 
head  of  NSABP  pending  the  ongoing  reviews  and  reforms.  Dr. 
Herberman,  who  served  as  an  NIH  scientist  for  many  years  before 
coming  to  the  University  of  Pittsburgh,  agreed  to  take  on  this 
heavy  and  thankless  burden,  making  only  the  request,  which  we 
will  honor,  that  as  soon  as  a  permanent  NSABP  chair  is  in  place 
he  will  return  to  his  duties  as  head  of  the  Pittsburgh  Cancer  Insti- 
tute. 

We  are  committed  to  finding  the  best  possible  candidate  to  be 
permanent  NSABP  chair  and  are  now  conducting  a  national  search 
for  a  nationally  recognized  and  distinguished  surgical  oncologist  to 
serve  in  that  role. 

We  have  proposed  and  are  committed  to  the  implementation  of 
a  new  permanent  NSABP  leadership  structure  to  ensure  that  the 
project  will  be  run  in  a  manner  that  justifies  high  public  con- 
fidence. 

NSABP,  under  the  interim  leadership  of  Dr.  Herberman  and  his 
colleagues,  proposed,  and  the  National  Cancer  Institute  accepted — 
after  many  extensive  and  substantive  interactions — a  comprehen- 
sive NSABP  plan  for  corrective  actions.  Dr.  Herberman  will  de- 
scribe the  highlights  of  that  plan  to  you.  I  will  comment  only  that 
the  plan  includes  some  of  the  most  innovative,  reliable  and  state- 
of-the-art  data  integrity  and  audit  mechanisms  known  to  science  in 
the  context  of  the  multi-center  clinical  trial. 

We  have  responded  openly  and  cooperatively  to  the  requests  of 
this  subcommittee  and  its  staff  for  documents,  information  and  wit- 
ness interviews  and  have  similarly  responded  to  requests  from 
what  I  believe  you  refer  to  as  the  other  body. 

As  has  been  reported  in  the  press,  the  University  convened  an 
independent  panel  of  nationally  recognized  experts  to  determine 
whether  an  investigation  is  warranted  into  possible  scientific  mis- 
conduct by  several  NSABP  personnel.  That  panel  is  hard  at  work, 
and  we  are  giving  them  all  of  the  data  and  support  that  they  need 
and  want. 

As  you  know,  Mr.  Chairman,  and  as  we  have  discussed  with  the 
subcommittee  staff,  the  University  is  bound  by  applicable  HHS  reg- 
ulations to  maintain  the  confidentiality  of  the  misconduct  inquiry 
and  to  preserve  the  due  process  rights  of  the  individuals  involved, 
who  are  represented  by  their  own  attorneys. 

NSABP,  NCI,  NIH,  HHS  and  the  University  of  Pittsburgh  per- 
sonnel, in  response  to  these  important  issues,  have  met  and  talked 


137 

by  telephone  innumerable  times,  exchanged  detailed,  voluminous 
information  and  worked  continuously  to  get  the  facts,  analyze  the 
issues  and  meet  all  concerns.  This  work  is  ongoing,  but  I  can  report 
that  very  extensive  and  positive  progress  has  been  made. 

Mr.  Chairman,  I  will  tell  you  frankly  that  over  the  past  several 
months  I  have  often  asked  myself  what  I  could  have  and  should 
have  done  to  prevent  the  concerns  that  we  are  addressing  today 
about  NSABP's  administration.  That  question  has  taken  me  down 
many  pathways  of  self-examination,  self-interrogation,  and  some- 
times self-doubt. 

Although  I  have  many  flaws,  being  timid  is  not  one  of  them.  Had 
I  been  motivated  to  probe  the  management  of  NSABP  more  deeply, 
I  would  certainly  have  done  so.  Why  did  I  not? 

The  answer  to  this  question  why  did  I  not  is  neither  easy  nor 
clear,  and  I  do  not  yet  have  complete  confidence  in  the  answer  even 
now.  The  answer,  I  believe,  primarily  relates  to  the  culture  of  def- 
erence that  has  developed  at  universities  over  many,  many  years, 
if  not  centuries.  The  modem  research  university,  although  subject 
to  strict  accountability  to  government  and  the  public,  is  primarily 
a  highly  decentralized  system  for  research  and  teaching  in  which 
faculty,  and  especially  well-established  senior  faculty,  have  very 
considerable  autonomy. 

Are  we  at  the  University  of  Pittsburgh  behind  the  curve  in  this 
respect?  I  commissioned  an  informal  survey  of  20  leading  American 
research  universities  to  find  the  answer  to  this  question.  What  I 
learned  is  that,  with  the  possible  exceptions  of  two  universities, 
none  of  these  leading  institutions  has  in  place  a  systematic,  peer- 
driven  mechanism  for  reviewing  the  adequacy  of  research  adminis- 
tration by  senior  faculty.  That  finding  did  not  surprise  me. 

As  I  pointed  out  in  an  interview  some  weeks  ago  to  The  New 
York  Times,  the  time  has  come  to  give  very  serious  consideration 
to  changing  this  culture  of  deference.  This  matter  requires  thor- 
ough examination  within  the  higher  education  community  in  gen- 
eral and  the  biomedical  research  community  in  particular.  My 
guess  is  that  this  culture  of  deference,  as  Dr.  Broder  pointed  out 
in  his  April  13th  testimony  to  the  subcommittee,  made  him  hesi- 
tate to  call  upon  the  senior  academic  administration  of  our  Univer- 
sity when  NCI  did  not  get  a  satisfactory  response  from  NSABP. 

I  will  propose  at  the  University  of  Pittsburgh,  Mr.  Chairman,  a 
potent  mechanism  for  peer  review  of  the  adequacy  of  administra- 
tion by  principal  investigators,  including  senior  faculty.  We  will  use 
this  new  mechanism  as  a  pilot  program  or  model.  Dr.  O'Connor 
supports  our  efforts,  and  I  expect  that  our  faculty  will  support 
them  as  well  when  the  merit  of  this  initiative  is  presented. 

Mr.  Chairman,  I  also  wish  to  say  a  word  about  research  mis- 
conduct. We  have  taken  very  aggressive  efforts  at  the  University 
of  Pittsburgh  to  deter  such  misconduct  and  to  encourage  the  report- 
ing of  alleged  research  misconduct.  We  have  had  several  cases  that 
resulted  in  a  finding  of  misconduct  and  on  the  whole  handled  them 
to  the  best  of  our  ability,  learning  sometimes  the  hard  way  from 
our  experience. 

I  might  note  that  only  two  of  our  cases  involved  fabrication  or 
falsification  of  data  included  in  published  research,  like  the  case 
from  Montreal  that  first  brought  the  NSABP  matter  to  our  atten- 


138 

tion.  It  is  extremely  difficult  and  perhaps  impossible  to  judge  reli- 
ably whether  a  particular  institution  has  more  or  less  research 
misconduct  than  another  institution.  However,  common  sense  sug- 
gests that  there  will  be  more  misconduct  proceedings  at  institu- 
tions that  are  alert  to  misconduct  and  report  it  competently,  ener- 
getically and  efficiently.  Generalizations  are  hazardous  about  these 
matters  and  especially  about  the  highly  diverse  and  relatively  few 
cases  we  have  experienced  at  the  University  of  Pittsburgh. 

A  legitimate  question  has  also  arisen  whether  it  was  sound  policy 
to  accept  philanthropic  funds  from  a  pharmaceutical  company  to 
endow  a  proposed  professorial  chair  when  a  product  of  the  pharma- 
ceutical company  was  being  researched  at  the  University  and  by 
the  professor  in  whose  honor  the  chair  was  to  be  named. 

On  the  issue  of  conflict  of  interests  and  the  Bernard  Fisher-ICI 
Pharma  Professorship  in  Surgery — which  to  the  present  day  has 
never  been  fully  funded  or  activated — we  simply  ask,  as  has  the 
scientific  community,  that  the  government's  standards  in  this 
evolving  area  be  made  clear  and  be  applied  prospectively,  not  retro- 
actively. Researchers  and  the  institutions  at  which  they  work  can 
adjust  to  any  reasonable  standards,  but  it  is  counterproductive  to 
judge  them  by  standards  not  in  effect  now,  let  alone  years  ago. 

Mr.  Chairman,  like  virtually  every  other  research  University  in 
the  United  States,  the  University  of  Pittsburgh,  no  less  than  NIH, 
Congress  and  the  American  people,  is  deeply  concerned  whenever 
administration  of  any  of  its  programs  falls  short  of  sustained  excel- 
lence, whether  slightly  short  or  far  short.  The  facts  are  still  not  all 
in,  but,  like  the  National  Cancer  Institute,  we  acknowledge  and  are 
addressing  in  detail  deficiencies  and  objectives  for  improvement. 

The  University  of  Pittsburgh's  fundamental  aim  in  relation  to 
this  matter  is  neither  to  defend  nor  to  accuse  but  to  determine  dis- 
passionately, fully  and  as  speedily  as  feasible  what  happened,  what 
can  be  learned  from  it  and  what  remedial  actions  are  appropriate 
and  proportional  to  past  performance  and  future  commitment.  To 
that  end,  we  are  hard  at  work,  and  we  will  remain  at  work  until 
we  have  satisfactory  answers. 

Thank  you  very  much,  Mr.  Chairman. 

Mr.  DiNGELL.  Thank  you.  Dr.  Detre. 

Dr.  Herberman. 

TESTIMO^fY  OF  RONALD  B.  HERBERMAN 

Mr.  Herberman.  Mr.  Chairman  and  members  of  the  subcommit- 
tee, I  am  Dr.  Ronald  Herberman,  and  I  am  pleased  to  be  here 
today  to  talk  about  the  National  Surgical  Adjuvant  Breast  and 
Bowel  Project,  the  NSABP. 

As  interim  chairman,  I  wish  to  briefly  address  its  past,  its 
present  and  its  future.  I  have  provided  more  detailed  remarks  for 
you  to  peruse  at  your  leisure. 

Mr.  DiNGELL.  Without  objection,  those  will  be  inserted  in  the 
record  at  the  appropriate  place. 

Mr.  Herberman.  Thank  you,  sir. 

First  and  foremost,  my  goal  as  a  cancer  researcher  as  well  as  in- 
terim chairman  of  the  NSABP  is  to  see  that  this  organization  re- 
mains viable  and  effective.  The  NSABP  must  continue  to  develop 


139 

and  implement  innovative  clinical  trials,  trials  designed  to  advance 
the  treatment  and  prevention  of  breast  and  colorectal  cancer. 

The  NSABP  is  a  most  important  research  program.  It  needs  to 
be  preserved  and  restored  to  its  full  vitality. 

Since  March  30th,  when  I  was  asked  by  the  University  of  Pitts- 
burgh and  by  the  National  Cancer  Institute  to  assume  administra- 
tive responsibility  for  this  program,  I  have  felt  it  my  obligation  to 
be  certain  that  what  the  NSABP  accomplishes  will  truly  be  in  the 
national  interests.  Primarily,  it  has  to  operate  in  the  best  interests 
of  those  women  and  men  affected  by  breast  or  bowel  cancer.  In  this 
regard,  we  have  taken  appropriate  steps  to  move  the  organization 
forward  and  to  restore  confidence  in  the  future  of  the  NSABP. 

Let  me  tell  you  about  my  initial  reaction  when  I  assumed  respon- 
sibility for  the  NSABP.  I  found  an  organization  under  siege.  There 
was  widespread  concern.  This  came  from  both  the  NCI  and  the 
public.  It  dealt  with  a  variety  of  problems  that  the  group  had  not 
adequately  handled,  but  I  also  knew,  as  a  cancer  researcher — in 
fact,  director  of  the  Pittsburgh  Cancer  Institute — that  this  multi- 
center  clinical  trials  group  had  a  proud  history.  It  had  to  its  credit 
a  series  of  pioneering  and  even  ground-breaking  discoveries  relat- 
ing to  cancers  of  the  breast,  colon  and  rectum. 

My  immediate  goal  was  to  stabilize  the  program  and  to  keep  it 
on  track.  I  believe  that  in  a  short  period  of  only  10  weeks  that  we 
have  been  together  our  new  team  has  accomplished  a  series  of 
major  steps  towards  restoring  credibility.  Yes,  I  believe  we  are  get- 
ting the  program  back  on  track. 

When  I  began  my  remarks  I  mentioned  I  would  discuss  the  past, 
present  and  the  future  of  the  NSABP.  Let  me  do  that  now  with 
some  specifics. 

Past:  You  know  about  the  deliberate  data  falsification  problems 
at  St.  Luc  Hospital  in  Montreal.  They  have  been  correctly  and  well 
documented. 

The  present:  We  are  putting  a  system  of  data  verification  in 
place  that  will  minimize  the  deliberate  and  also  inadvertent  errors. 

Data  falsification  is  reprehensible  and  cannot  be  tolerated,  par- 
ticularly when  it  may  impact  on  patient  welfare.  However,  in  terms 
of  effects  on  the  results  of  clinical  trials,  the  fact  is  that  it  doesn^t 
matter  if  a  mistake  is  deliberate  or  inadvertent.  You  must  mini- 
mize it  from  happening. 

Our  system  is  totally  unique  for  monitoring  clinical  trials  at  such 
a  large  number  of  institutions. 

The  future:  First  and  foremost,  it  will  involve  the  participants  in 
verifying  information  about  themselves.  When  someone  volunteers 
to  participate  in  a  clinical  study,  that  person  will  be  shown  a  list 
of  dates  of  key  events  that  will  determine  eligibility.  This  might  be 
the  date  of  surgery  or  the  date  when  a  mammogram  was  per- 
formed. 

This  procedure  is  indeed  revolutionary.  As  I  just  mentioned, 
something  like  this  has  never  been  incorporated  into  clinical  trials 
before.  If  this  had  been  in  place  previously,  this  rather  simple  step 
would  have  made  it  virtually  impossible  for  the  problems  at  St.  Luc 
to  have  occurred. 

So  already  we  have  taken  the  problem  of  misreporting  informa- 
tion, we  have  addressed  it  and  have  come  up  with  a  unique,  revolu- 


140 

tionary  solution.  This  system,  developed  in  cooperation  with  Wes- 
tinghouse  and  Carnegie  Group,  will  have  real-time  assessment  of 
a  patient's  status  and  proposed  treatment.  It  will  immediately 
bring  attention  to  deviations  or  inappropriate  actions. 

Let  me  show  you  this  new  system  briefly  in  greater  detail.  In 
other  words,  we  believe  that  this  is  the  future.  It  will  prevent  fal- 
sification of  data  and  prevent  inappropriate  procedures. 

By  the  way,  this  system  was  unveiled  earlier  this  week  at  the 
NSABP's  annual  meeting  in  Nashville.  More  than  a  hundred  data 
managers  from  participating  institutions  enthusiastically  endorsed 
the  approach,  and  many  of  them  were  vying  for  being  among  the 
sites  where  the  pilots  would  be  carried  out. 

Let  me  read  you  the  comments  from  one  of  the  data  managers 
at  this  meeting.  "We  have  been  requesting  software  like  this  for 
years  to  ensure  quality  data  at  our  fingertips  and  for  audits,  will 
make  data  collection  and  data  management  efficient,  will  provide 
continuity  and  quality  of  care,  great  job  done  in  6  weeks." 

Much  of  the  details  of  this  system  have  been  already  developed, 
and  this  has  been  done  in  close  consultation  with  cancer  survivors. 
We  have  put  together  an  advisory  committee  to  help  us  in  this  re- 
gard, and  I  will  leave  for  the  committee's  interest  a  videotape 
which  will  show  some  of  the  process  by  which  the  cancer  survivors 
helped  us  with  this  important  process. 

Mr.  DiNGELL.  Thank  you,  Doctor,  the  committee  will  receive  that, 
and  we  thank  you. 

Mr.  Herberman.  Thank  you,  Mr.  Chairman. 

Another  value  of  this  system  is  the  more  complete  informing  of 
clinical  trial  participants  about  their  disease,  their  proposed  treat- 
ments and  possible  consequences.  A  customized  notebook  will  be 
prepared  for  each  patient  electronically  which  will  include  informa- 
tion from  the  NCI's  PDQ  system  and  will  be  tailored  for  each  wom- 
an's individual  problems  and  the  proposed  treatments  so  that  each 
participant  on  a  clinical  trial  will  be  fully  informed. 

You  will  notice  that  this  is  in  a  loose-leaf  fashion.  This  will  be 
updated  at  every  visit  of  the  participant  to  see  the  doctors  and  the 
NSABP. 

A  third  issue  deals  with  the  drug  tamoxifen.  There  is  a  risk  in 
taking  most  drugs.  An  NSABP  study  itself  has  demonstrated  a  re- 
lationship between  the  use  of  tamoxifen  for  treating  breast  cancer 
and  the  development  of  uterine  cancer.  There  were  some  delays  in 
ascertaining  that  deaths  were  a  result  of  uterine  cancer.  Ways  have 
to  be  found  to  diagnose  uterine  cancer  early  to  prevent  progression 
and  even  death. 

Since  assuming  responsibility  we  did  two  major  things  in  this  re- 
gard. First,  we  established  an  independent  data  and  safety  mon- 
itoring question.  This  meets  regularly  and  reviews  all  information 
about  side  effects  from  any  treatments.  This  group  will  have  the 
power  to  make  appropriate  corrective  action  or  even  stop  the  trials 
until  problems  are  solved. 

Second,  we  have  developed  a  protocol  that  mandates  regular 
uterine  examination  on  all  new  participants  in  tamoxifen  trials. 
For  women  already  enrolled  on  a  tamoxifen  trial,  they  must  at 
least  be  told  about  the  recommendations  for  such  regular  monitor- 
ing. 


141 

By  the  way,  previous  NSABP  studies  have  clearly  indicated  the 
benefits  from  the  use  of  tamoxifen.  The  NSABP  trials  have  shown 
that  tamoxifen  is  highly  effective  in  preventing  recurrence  of  the 
original  breast  cancer.  At  the  same  time,  the  studies  demonstrated 
that  tamoxifen  went  a  long  way  in  preventing  a  new  cancer  in  the 
opposite  breast,  and,  in  fact,  this  important  finding  laid  the  founda- 
tion for  the  breast  cancer  prevention  trial  that  is  currently  being 
performed  by  the  NSABP. 

In  summary,  the  NSABP  has  certainly  had  its  share  of  chal- 
lenges— there  is  no  doubt  about  that — but  things  are  back  on  track. 
An  effective  quality  assurance  program  is  already  in  place.  In  fact, 
our  new  system  of  data  verification,  I  believe,  is  a  major  break- 
through. 

The  formation  of  oversight  and  also  data  and  safety  monitoring 
committees  add  greater  credibility  than  ever  before.  We  have  put 
steps  into  place  to  streamline  headquarters  operations  and  to  de- 
velop open  communications  with  patients  and  with  the  public.  The 
momentum  is  started  so  that  the  NSABP  can  continue  to  be  the 
high  quality  organization  it  was  meant  to  be.  I  can  assure  you  that 
the  NSABP  is  indeed  back  on  track. 

Thank  you  very  much,  Mr.  Chairman. 

[Testimony  resumes  on  p.  157.] 

[The  prepared  statement  of  Dr.  Herberman  follows:] 


142 

STATEMENT 
OF 


DR.  RONALD  B.  HERBERMAN 

INTERIM  CHAIRMAN 

NATIONAL  SURGICAL  ADJUVANT  BREAST  AND  BOWEL  PROJECT 


Mr.  Chairman  and  members  of  the  Subcommittee,  thank  you 
for  permitting  me  to  appear  before  you  today  and  provide  my  views 
as  the  Interim  Chairman  of  the  National  Surgical  Adjuvant  Breast 
and  Bowel  Project  ("NSABP"),  a  position  I  have  held  for  slightly 
more  than  two  months.   I  also  welcome  the  opportunity  to  answer 
your  questions  —  as  I  have  in  meetings  with  Subcommittee  staff 
—  and  to  provide  information. 

By  way  of  background  and  for  the  Subcommittee's 
information,  I  also  serve  as  the  Hillman  Professor  of  Oncology 
and  Professor  of  Medicine  and  Pathology  at  the  University  of 
Pittsburgh  and  as  Director  of  the  Pittsburgh  Cancer  Institute. 
The  Pittsburgh  Cancer  Institute  is  one  of  twenty-seven  federally- 
designated  comprehensive  cancer  centers  in  the  country.   It  is 
responsible  for  cancer  research  and  care  at  the  University  of 
Pittsburgh  Medical  Center.   Before  joining  PCI,  I  served  at  the 
National  Cancer  Institute  for  nineteen  years.   As  a  result  of  my 
work  in  these  positions,  I  have  extensive  experience  in 
clinically  relevant  cancer  research,  clinical  trials,  and 
research  administration. 

I  am  highly  honored  to  serve  as  Interim  Chairman  of 
NSABP,  especially  at  this  critically  challenging  time.  Although 
recent  events  have  understandably  focused  attention  on  NSABP 's 
past  administrative  deficiencies,  I  nevertheless  think  it 
appropriate  to  approach  the  leadership  of  this  organization  as  an 
act  of  stewardship  over  an  invaluable  national  resource  that  was 


143 


founded  and  nurtured  by  the  dedication  of  many  others:   Dr. 
Bernard  Fisher,  founder  and  former  Chair  of  NSABP,  who  has 
dedicated  his  entire  professional  life  to  eradicating  the  scourge 
of  breast  cancer;  Dr.  Carol  Redmond,  a  renowned  statistician  who 
has  created  and  managed  the  quantitative  foundation  of  the 
NSABP 's  research;  the  many  members  of  their  staff  at  the 
University  of  Pittsburgh  and  approximately  5000  researchers  at 
almost  five  hundred  other  facilities  participating  in  NSABP 
trials,  who  —  with  some  regrettable  exceptions  —  have  conducted 
the  massive  research  operation  that  is  NSABP  with  a  high  level  of 
dedication  and  professionalism;  the  federal  government  and 
taxpayers  who  provided  the  financial  resources  for  this  endeavor; 
and,  most  importantly,  the  50,000  or  so  women  who  have 
participated  in  the  numerous  NSABP  clinical  trials  that  have  so 
markedly  contributed  to  our  understanding  of  appropriate 
treatments  for  breast  cancer. 

Among  the  major  and  ground-breaking  innovations  that 
resulted  from  the  efforts  and  dedication  of  these  contributors 
are  studies  that  have:  1)  provided  evidence  supporting  the  use  of 
breast  conservation  surgery  as  an  alternative  to  radical 
mastectomy,  the  disfiguring  surgery  that  was  previously  the 
standard  procedure  in  cases  of  breast  cancer;  2)  demonstrated  an 
appropriate  role  for  chemotherapy  in  the  treatment  of  primary 
breast  and  colon  cancer;  and  3)  demonstrated  the  value  of  the 
drug  Tamoxifen  for  the  treatment  of  breast  cancer  and  the 
prevention  of  second  primary  cancers.   It  is  on  the  foundation  of 


-  2  - 


144 


these  and  other  significant  scientific  findings  that  we  now  work 
to  build  a  stronger  and  more  accountable  NSABP. 

Since  assuming  the  interim  chairmanship  of  NSABP  a 
little  more  than  two  months  ago,  I  have  been  engaged  more  than 
full  time  in  that  work.   A  wide  variety  of  issues  and  tasks  have 
arisen  on  a  number  of  fronts  during  that  time  period.  As  the 
interim  chairman  of  NSABP,  however,  I  have  primarily  focused  on 
two  key  priorities.   First,  one  of  my  main  tasks  in  the  last  two 
months  has  been  to  develop  open  communications  and  make  concerted 
efforts  to  restore  the  confidence  of  patients  and  the  public  in 
NSABP  clinical  trials  and,  derivatively,  in  clinical  trials 
generally.   Second,  and  in  service  of  the  first  priority,  I  have 
been  working,  together  with  Dr.  Donald  Trump,  Interim  Executive 
Officer  of  NSABP  as  well  as  Deputy  Director  of  the  Pittsburgh 
Cancer  Institute,  to  understand  the  administrative  and  other 
problems  that  exist  at  NSABP  and  to  respond  by  developing 
detailed  plans  to  ensure  that  these  problems  cannot  occur  in  the 
future. 

Let  me  first  mention  generally  the  types  of  problems  we 
have  identified.  As  made  clear  by  the  entire  St.  Luc  episode  — 
and  several  other,  less  dramatic,  episodes  that  have  subsequently 
come  to  light  —  NSABP  unfortunately  suffered  from  a  number  of 
deficiencies  in  quality  assurance  and  also  administrative  and 
reporting  lapses  in  the  face  of  problems  that  were  detected  in 
audits  of  institutions  outside  Pittsburgh  that  enroll  patients  in 
NSABP  studies.   On  some  occasions,  for  example,  questions 

-  3  - 


145 


concerning  the  eligibility  of  patients  to  participate  in  various 
NSABP  clinical  trials  were  identified  at  the  time  of  an  audit  but 
not  properly  resolved.  Most  of  the  identified  problems  may  be 
grouped  into  two  categories,  one  focused  on  several  of  the  almost 
500  institutions  around  the  United  States  and  Canada 
participating  in  the  clinical  trials,  and  one  reflecting 
deficiencies  in  the  NSABP  Headquarters: 

1.  Deliberate  or  inadvertent  errors  in  data 
affecting  eligibility  or  other  important  aspects 
of  the  studies.   Whether  such  errors  are 
deliberate  or  a  result  of  sloppiness  in  record 
keeping,  they  detract  from  the  research  and  must 
be  minimized;  and 

2.  Slow  or  ineffective  handling  of  the  problems 
once  they  are  detected  by  Headquarters  staff. 

Each  such  deficiency  is  of  urgent  concern.   Let  me 
stress,  however,  that  nothing  we  have  discovered  during  this 
period  of  intense  scrutiny  has  provided  any  basis  to  doubt  the 
fundamental  findings  of  NSABP 's  various  ground-breaking  studies. 
In  fact,  various  independent  clinical  trials  and  also  reanalyses 
of  the  NSABP  data  —  both  within  and  without  NSABP  —  have 
confirmed  all  of  the  major  conclusions  from  those  studies. 


-  4  - 


146 


In  addition,  as  NCI  has  known  for  some  time,  NSABP  had 
in  the  last  year  fallen  significantly  behind  schedule  in 
performing  the  audits  of  institutions.   While  there  may  have  been 
some  plausible  reasons  for  this  problem,  including  the  shift  to 
implementation  during  the  last  year  of  a  new  and  improved  NSABP 
auditing  system,  we  simply  cannot  tolerate  gaps  in  verification 
of  information  and  practices  at  participating  institutions.   In 
light  of  the  particular  concerns  that  have  been  expressed 
concerning  the  gathering  and  handling  of  information  relating  the 
use  of  Tamoxifen  to  increased  risk  of  developing  endometrial 
cancer,  we  have  also  been  re-examining  intensively  the  entire 
NSABP  system  for  identifying  and  reporting  adverse  drug  reactions 
that  may  be  experienced  by  patients  enrolled  in  NSABP  protocols. 

These  are  some  of  the  types  of  problems  we  have 
identified  in  our  efforts  to  make  NSABP  a  stronger  and  more 
accountable  research  organization.   In  response  to  these  problems 
and  others,  however  —  and  in  the  midst  of  crushing  demands  for 
information  from  various  government  entities  and  the  press  —  we 
have  in  the  space  of  two  short  months  implemented  a  number  of 
significant  structural  and  administrative  changes  that  we  believe 
will  both  address  these  problems  directly  and  restore  the 
confidence  of  participants  in  NSABP  clinical  trials,  the  breast  . 
and  bowel  cancer  community,  the  scientific  community  generally, 
and  the  public  at  large.   These  actions  and  proposals  for  further 
action  are  explained  in  detail  in  the  "NSABP  Plan  for  Corrective 
Actions"  that  was  submitted  to  NCI  on  May  24.   A  copy  of  this 


-  5  - 


147 


Plan  has  been  provided  to  the  Committee  for  its  information.   I 
summarize  here  some  of  the  key  components  of  this  plan. 

Working  closely  with  Dr.  Samuel  Broder,  Director  of 
NCI,  Dr.  Bruce  Chabner,  Director  of  NCI's  Division  of  Cancer 
Treatment,  and  other  NCI  officials,  we  have  established  the  NSABP 
Oversight   Cconmlttee  as  an  external  advisory  group.   Members  of 
the  Committee  include  experts  in  large-scale,  clinical  cancer 
trials.   Of  particular  significance,  moreover,  the  Committee 
includes  two  lay  members  who  serve  as  advocates  for  breast  cancer 
patients  and  survivors:   Amy  Langer,  Executive  Director  of  the 
National  Alliance  of  Breast  Cancer  Organizations,  a  member  of  the 
Board  of  Directors  of  the  National  Breast  Cancer  Coalition,  and  a 
breast  cancer  survivor;  and  Dorothy  Raizman,  an  attorney  who  is  a 
recognized  authority  on  medical  records  and  the  communication  of 
information  within  and  throughout  the  medical  system.   The  NSABP 
Oversight  Committee  is  advising  me  on  reorganization  of  the  NSABP 
leadership  structure,  and  will  continue  in  place  at  least  until 
the  NSABP  is  stabilized  and  functioning  more  effectively. 

With  the  assistance  of  the  NSABP  Oversight  Committee, 
we  have  proposed  a  plan  for  a  new  NSABP  leadership  structure.      We 
are  working  on  revisions  of  the  NSABP  constitution  and  bylaws 
that  will  shift  a  good  deal  of  responsibility  for  management  of 
NSABP  from  the  group  Chair  to  a  reconstituted  Executive 
Committee.   The  Executive  Committee  membership  will  be  more 
broadly  representative  of  all  group  constituencies  than  the 
current  Executive  Committee.   Following  reconstitution  of  the 

-  6  - 


148 


Executive  Committee,  that  body  will  nominate  candidates  for  a  new 
permanent  group  Chairman,  and  this  important  step  will  be 
followed  by  an  election  by  the  membership  of  the  group,  and 
approval  of  the  selection  by  the  National  Cancer  Institute. 

A  major  goal  of  our  revised  leadership  structure  is  to 
ensure  greater  participation  by  the  health  care  providers  and 
researchers  In  local  NSABP  centers  In   the  design  and  execution  of 
research  protocols .      I  hasten  to  note  that,  even  under  the  former 
management  structure,  protocol  design  committees  and  the  NSABP 
group  meetings  have  generally  provided  excellent  opportunities 
for  group-wide  participation  in  protocol  design.   Our  proposed 
management  structure  will  further  enhance  membership  involvement 
by  establishing  standing  disease-specific  (breast  or  colorectal) 
committees,  each  with  a  chair  empowered  to  review  continuously 
the  status  of  ongoing  trials,  solicit  group-wide  and  ad  hoc 
external  input,  and  guide  development  of  new  protocol  concepts. 
These  committees  will  be  responsible  to  the  Executive  Committee, 
which,  as  noted,  will  itself  have  broader  membership  and  more 
inclusive  group  representation  than  under  its  current  structure. 

We  have  also  established  a  Data  and  Safety  Monitoring 
Committee,    the  membership  of  which  is  completely  independent  of 
NSABP.   The  primary  responsibility  of  this  Committee  is  to  review 
interim  analyses  of  outcome  data  and  to  recommended  changes  in  — 
or  termination  of  —  studies  based  on  these  analyses.   The 
Committee  will  also  review  toxicity  data,  major  modifications  of 
studies,  NSABP  handling  of  scientific  misconduct,  NSABP  quality 

-  7  - 


149 


assurance,  and  consent  form  issues  related  to  toxicities. 
Included  as  a  member  of  this  Committee  is  Kay  Dickersin,  Ph.D., 
Department  of  Ophthalmology,  University  of  Maryland,  who  is  a 
breast  cancer  advocate  and  survivor,  with  considerable  expertise 
in  clinical  trials  and  epidemiology. 

In  consultation  with  NCI  and  experienced  auditors  from 
other  cooperative  groups,  we  have  also  developed  an  improved  on- 
site  monitoring  and  quality  assurance  program.   Under  these  aaw 
audit  procedures,    an  institution  will  be  notified  four  weeks  in 
advance  of  a  proposed  audit,  and  will  be  informed  two  weeks  in 
advance  as  to  which  cases  are  to  be  audited.   These  cases  are 
randomly  selected,  and  additional  cases  are  identified  on  site  at 
the  time  of  the  audit.   Document  review  will  occur  on  site, 
rather  than  at  NSABP  as  under  the  former  system.   Each  audit  team 
will  include  an  independent  member  and  NSABP  group  members  will 
be  involved  in  the  actual  performance  of  the  audits.   To  assist 
in  the  implementation  of  these  new  procedures,  we  have 
subcontracted  with  a  consulting  firm  experienced  in  the  auditing 
of  oncology  trials. 

NSABP  will  notify  the  Clinical  Trials  Monitoring  Branch 
("CTMB")  of  NCI  of  any  major  deviation  within  24  hours  of 
discovery,  and  will  send  by  facsimile  the  preliminary  audit 
finding  within  24  hours  of  completion  of  the  audit.   Within  seven 
days  of  the  auditors'  return  and  after  review  by  the  Executive 
Officer,  NSABP  will  transmit  an  audit  summary  to  NCI  and  the 
audited  institution.   The  institution  will  then  be  given  20  days 

-  8  - 


150 


to  respond.   Within  30  days  of  the  preliminary  report  and  after 
approval  by  the  Quality  Assurance  Committee,  a  final  report 
containing  the  Executive  Officer's  recommendations  will  be  sent 
to  NCI  and  the  institution.   All  institutions  will  be  at  risk  of 
annual  audits,  and  will  be  audited  at  least  once  every  three 
years . 

NSABP  has  proposed  a  schedule  that  will  eliminate  the 
back-log  of  audits  by  April  1,  1995,  with  highest  priority  given 
to  institutions  with  large  numbers  of  accruals,  previously 
recognized  problems,  or  a  gap  of  more  than  three  years  since  the 
previous  audit.   A  review  of  past  audits  will  be  used  to  identify 
outstanding  issues  and  priorities  for  future  audits.   NSABP  will 
provide  NCI  semi-annually  an  updated  list  of  institutions  to  be 
audited  within  the  next  six  months.   New  procedures  are  being 
developed  to  provide  for  timely  auditing  of  low-accruing 
institutions  and  small  affiliates. 

In  response  to  problems  identified  in  past  audits, 
NSABP  has  assisted  NCI  in  organizing  re-audits,  followed  up  on 
identified  deficiencies,  and  taken  significant  corrective 
measures.   In  addition,  we  have  initiated  a  broad  scale  review  of 
all  previously  conducted  audits  —  and  NSABP 's  handling  of 
deficiencies  identified  by  those  audits  —  to  further  ensure  that 
all   questions  involving  quality  assurance  are  appropriately 
resolved. 


-  9  - 


151 


We  have  also  been  examining  ways  to  increase  the 
reliability  of  information  at  the  time  it  is  initially  entered 
into  the  NSABP  process.   Calling  upon  existing  relationships  with 
the  Westinghouse  Electric  Corporation's  Science  and  Technology 
Center  and  Carnegie  Group,  Inc.  Dr.  Trump  and  I  have  worked  to 
generate  new  processes  for  handling  data  monitoring  and  quality 
control  issues.   I  should  note  that  we  began  to  develop  these 
processes  over  a  year  ago,  well  before  the  current  controversy 
over  NSABP  arose.   One  important  new  procedure  will  involve 
patients  —  who  likely  are  in  the  best  position  to  verify  certain 
information  —  in  quality  control  procedures  incorporating 
important  patient  history  dates  into  the  consent  form  for  patient 
verification.   The  University  of  Pittsburgh  has  also  been  working 
with  Westinghouse  and  the  Carnegie  Group  to  develop  a  prototype 
system  for  data  confirmation  and  quality  control,  which  was 
demonstrated  earlier  this  week  to  investigators  and  data  managers 
at  the  NSABP  group  meeting  in  Nashville.   Improvement  of  this 
information  process  continues,  and  a  pilot  test  and  verification 
of  its  effectiveness  are  planned. 

One  of  our  primary  concerns  is  to  Increase  the 
invol-vemeat  of  breast  and  colorectal  cancer  survivors  and   their 
advocates  in   the  NSABP.      A  comprehensive  plan  to  achieve  this 
goal  is  being  developed  and  will  be  presented  to  NSABP  members  at 
our  group  meeting  later  this  month.   Under  this  innovative  plan, 
representatives  of  these  groups  will:   1)  attend  and  participate 
in  each  NSABP  membership  meeting;  2)  serve  on  protocol 


-  10 


152 


development  committees;  3)  serve  on  focus  groups  to  provide  input 
on  protocol  design,  informed  consent  documents,  and  audit 
procedures;  and  4)  participate  in  the  development  of  plans  for 
assessing  such  issues  as  effects  of  clinical  trials  on  quality  of 
life,  compliance  of  patients  on  clinical  protocols,  and 
psychological  aspects  of  clinical  trials.   We  will  also  develop  a 
procedure  to  inform  participants  in  a  trial  and  their  families 
about  the  results  of  a  trial  as  they  are  published.   We  hope  to 
establish  a  close  and  ongoing  partnership  between  patients  and 
their  physicians,  and  to  ensure  that  patients  are  fully  educated 
about  the  clinical  trials  in  which  they  participate. 

Let  me  also  mention  some  specific  actions  we  have  taken 
in  responso  to  St.    Luc   falsifications  and  the  questions  about 
whether  those  were  adequately  disclosed.   NSABP  officials 
previously  had  determined  (in  July  1991)  that  the  falsified  data 
did  not  affect  study  outcomes,  and  had  given  a  presentation  to 
NCI  officials  in  March  1992  on  their  statistical  reanalysis  of 
data  from  four  NSABP  trials,  excluding  falsified  data  from  St. 
Luc  Hospital.  Although  NCI  and  ORI  had  asked  NSABP  to  prepare  a 
reanalysis  for  publication  immediately  following  the  conclusion 
of  OKI's  investigation  into  St.  Luc,  the  reanalysis  was  not 
assigned  the  priority  that  it  merited.   NSABP  submitted  the 
formal  manuscript  to  NCI  on  February  8,  1994. 

On  March  17,  1994  Dr.  Fisher  notified  the  New  England 
Journal  of  Medicine  ("NEJM")  that  papers  published  in  that 
journal  concerning  three  NSABP  trials  contained  falsified  data 

-  11  - 


153 


from  St.  Luc.   NSABP  had  mistakenly  decided  not  to  notify  NEJM  of 
the  ORI  findings  earlier  because  those  findings  had  been 
published  in  the  Federal  Register,  because  Drs.  Fisher  and 
Redmond  were  preparing  a  formal  paper  for  submission  to  NEJM,  and 
because  the  falsified  data  did  not  affect  the  study  results.   The 
University  acknowledged  that  this  was  a  mistake  in  a  March  28, 
1994  letter  to  the  editor  of  NEJM.   On  March  25,  after  NCI's 
review,  the  paper  reanalyzing  data  from  the  three  trials  was 
submitted  to  NEJM  for  publication. 

On  March  30,  Dr.  Fisher  notified  in  writing  all  other 
journals  that  had  published  articles  including  fraudulent  St.  Luc 
data  since  1991.   NSABP  withdrew  manuscripts  including  tainted 
data  that  had  been  submitted  or  were  in  press.   On  April  7,  1994, 
we  sent  all  principal  investigators  a  summary  of  ORI ' s  findings 
regarding  St.  Luc  and  a  model  letter  to  patients  reassuring  them 
of  the  validity  of  the  study  results  and  acknowledging  the 
misperception  creatied  by  NSABP 's  delay  in  publicizing  the 
problem.   On  May  6,  1994  I  wrote  to  the  editors  of  all  affected 
journals  and  affirmed  NSABP 's  commitment  to  reanalyzing  the  trial 
data  and  confirming  the  studies'  validity. 

NSABP  currently  is  preparing  a  manuscript  describing 
the  reanalysis  of  all  affected  trials.   This  reanalysis  will  be 
provided  for  NCI's  review  by  June  30,  1994  and  submitted  for 
publication  upon  NCI's  approval.   A  detailed  description  of  the 
reanalysis  appeared  in  a  Technical  Report  distributed  at  our 
NSABP  meeting  (which  was  held  over  the  last  several  days)  and  is 

-  12  - 


154 


being  made  available  to  journals  that  have  published  reports 
including  St.  Luc  data.   Each  if  these  journals  will  also  receive 
notices  of  the  formal,  published  reanalysis.  At  our  recent  NSABP 
meeting,  we  had  an  extensive  discussion  of  the  St.  Luc  incident, 
which  I  believe  served  to  educate  NSABP  physicians,  data 
monitors,  and  support  staff  about  the  St.  Luc  problem,  the 
ethical  and  legal  consequences  of  scientific  fraud,  and  NSABP' s 
new  procedures  for  preventing  and  detecting  data  falsification. 
A  letter  describing  the  St.  Luc  problem  has  been  developed  in 
consultation  with  breast  cancer  advocates  and  sent  to  a  wide 
range  of  individuals  and  organizations. 

With  respect  to  problems  at  other  institutions,  I  think 
it  is  important  to  stress  that  none  of  the  other  cases  we  are 
examining  have  been  determined  to  involve  the  type  of  deliberate 
and  systemic  falsifications  that  were  identified  at  St.  Luc, 
although  investigation  is  ongoing.  That  does  not,  of  course, 
diminish  in  the  least  the  need  to  address  data  integrity  issues, 
for  we  should  strive  to  eliminate  all  error  —  whether  deliberate 
or  inadvertent  —  from  our  data  set. 

In  connection  with  the  discovery  of  evidence  of 
possible  scientific  misconduct  at  St.  Mary's  Hospital  in 
Montreal,  NSABP  has  worked  to  correct  the  problems  leading  to  a 
delay  in  reporting  that  evidence  to  NCI,  and  has  provided  NCI 
with  information  and  assistance  in  re-auditing  St.  Mary's.   ORI's 
investigation  into  evidence  of  scientific  misconduct  at  St. 
Mary's  is  expected  to  conclude  in  the  near  future. 

-  13  - 


155 


Administrative  problems  that  have  been  identified 
during  audits  of  Louisiana  State  University  ("LSU")  and  Tulane 
University  led  to  suspension  of  these  institutions  that  month, 
prior  to  the  general  suspensions  of  NSABP  institutions.   These 
problems  have  been  identified  to  the  principal  investigators  at 
LSU  and  Tulane,  whose  responses  and  proposals  for  solving  the 
problems  will  be  addressed.   Dr.  Trump  as  Interim  Executive 
Officer  is  reviewing  these  responses  and  together  with  NSABP 
staff  will  determine  whether  accrual  at  these  sites  should  be 
resumed.   We  have  also  been  working  with  NCI  to  address  problems 
relating  to  Memorial  Cancer  Research  Foundation  in  Los  Angeles 
and  its  principal  investigator.  Dr.  David  Plotkin,  and  South 
Nassau  Community  Hospital. 

We  are  well  aware  that  NCI  has  perceived  an 
unresponsiveness  or  inadequate  responsiveness  from  NSABP  in  the 
past,  particularly  in  the  administrative  realm.   That  perception, 
whatever  the  basis  for  it,  is  destructive  of  the  close  working 
relationship  with  the  funding  agency  that  is  necessary  to  the 
conduct  of  federally  sponsored  research.   We  have  taken  very 
substantial  and  concrete  steps  to  ensure  responsiveness  to  NCI, 
and  to  prevent  such  a  perception  henceforth. 

I  should  also  mention,  as  has  been  reported  in  the 
press,  that  the  University  has  initiated  a  scientific  misconduct 
inquiry  relating  to  events  and  actions  at  NSABP.   A  highly 
distinguished  three-njember  panel  has  been  convened.   Each  of  the 
panelists  is  a  nationally  recognized  authority,  based  at  another 

-  14  - 


156 


institution,  holds  no  position  at  the  University  of  Pittsburgh, 
and  is  independent  of  both  the  University  and  NSABP.   The  purpose 
of  the  preliminary  inquiry  is  to  determine  whether  a  formal 
investigation  of  this  matter  as  a  scientific  misconduct  case  is 
warranted.   Fairness  to  the  respondents  in  that  inquiry  compels 
me  to  refrain  from  further  comment. 

As  I  said  at  the  outset,  I  view  my  service  to  NSABP  as 
an  act  of  stewardship  over  a  valuable  national  resource.   It  is 
my  firm  belief  that  the  actions  I  have  described,  and  the  path  we 
are  now  on,  will  not  only  preserve  that  resource  from 
deterioration,  but  will  also  nurture  and  rejuvenate  NSABP  so  that 
it  may  continue  and  expand  its  service  to  the  women  of  this 
nation  for  years  to  come.   I  am  pleased  that  we  have  made  such 
significant  progress  that  we  were  permitted  last  week  to  announce 
that  NSABP  will  begin  to  accrue  patients  once  again  into  its 
vitally  important  clinical  trials.   I  look  forward  to  working 
with  the  Members  of  this  Subcommittee,  NIH,  NCI,  and  breast  and 
bowel  cancer  patients  and  their  advocates,  to  ensure  that  this 
step  is  only  the  initial  evidence  of  the  successful 
reorganization  of  the  NSABP. 

I  would  be  pleased  to  answer  any  questions  you  may 
have. 


-  15  - 


157 

Mr.  DiNGELL.  Gentlemen,  the  Chair  wants  to  thank  you  for  your 
very  fine  statements. 

Dr.  O'Connor,  as  you  indicated,  the  committee  has  sharp  teeth, 
and  we  don't  always  like  to  use  them  on  people,  but  occasionally 
these  things  happen.  I  want  to  commend  you  and  you,  Dr.  Detre, 
and  you,  Dr.  Herberman,  for,  first,  fine  statements;  second  of  all, 
to  tell  you  that  the  staff  and  I  have  appreciated  the  way  that  you 
have  worked  with  us  and  we  have  worked  with  you  to  address  the 
concerns  of  the  committee  and  to  tell  you  that,  from  your  state- 
ments and  from  what  we  have  seen  as  we  have  worked  moving  to- 
wards these  hearings,  my  belief  that  the  process  of  scientific  review 
and  supervision  and  auditing  will  move  much  forward  because  of 
the  good  work  which  you  have  done  and  are  doing,  and  we  com- 
mend you  for  that.  Thank  you. 

Mr.  O'Connor.  Thank  you. 

Mr.  DiNGELL.  The  Chair  does  have  some  questions,  and  the 
Chair  advises  that  the  Chair  will  be  recognizing  members  for  10 
minutes  rather  than  5  in  order  to  address  the  questions  that  we 
have  before  us. 

I  would  like  to  observe  to  you.  Dr.  Detre,  that  I  come  from  a  part 
of  the  country  where  accents  are  common.  And  we  are  not  only 
comfortable  with  them,  but  we  think  that  our  best  and  most  pro- 
ductive people  very  frequently  have  accents.  And  we  are  com- 
fortable with  them,  and  we  rejoice  that  we  have  people  who  have 
accents  who  can  make  meaningful  and  good  contributions.  So  I  am 
comfortable  with  it,  and  I  hope  you  are,  too. 

Mr.  Detre.  Thank  you,  sir. 

Mr.  DiNGELL.  First  of  all.  Dr.  Detre,  since  this  situation  unfolded 
the  University  of  Pittsburgh  has  initiated  a  number  of  separate  re- 
views or  investigations  which  have  been  referred  to  in  the  com- 
ments of  yourself,  Dr.  O'Connor  and  Dr.  Herberman.  Without  dis- 
cussing the  questions  of  scientific  misconduct  in  that  investigation 
that  is  currently  under  way,  could  you  describe  in  general  what  you 
found  regarding  the  management  and  administration  of  NSABP? 

Mr.  Detre.  Yes,  Mr.  Chairman,  that  is  a  very  important  ques- 
tion. Literally  every  component  of  the  NSABP  functions  reasonably 
well,  but  the  coordination  among  the  various  functions  showed  con- 
siderable deficiencies.  This,  in  turn,  led  to  delayed  reporting  in 
some  instances  or  lack  of  reporting  in  others. 

Mr.  DiNGELL.  Now,  Dr.  Detre,  what  would  you  say  went  wrong 
with  management  and  administration  of  NSABP? 

Mr.  Detre.  Mr.  Chairman,  I  don't  think  I  can  be  more  precise 
about  it  except  to  say  that  the  administration  of  NSABP  needs 
some  reform.  Reform  which  would  ensure,  as  Dr.  Herberman  point- 
ed out,  that  the  database  for  clinical  research  begins  with  the  pa- 
tient, that  there  is  a  clear  trail  following  the  data  through  the  var- 
ious phases  of  the  treatment  trial  and  that  the  reporting  relation- 
ships are  clearly  defined  and  that  an  independent  mechanism  is  in 
place  to  ensure  that  not  just  the  audits  are  done  but  audit  reports 
arrive  through  the  proper  agencies  at  the  proper  time. 

Mr.  DiNGELL.  Dr.  Herberman,  we  understand  that  your  own  in- 
vestigations have  revealed  that  NSABP  was  violating  its  own  con- 
stitution with  respect  to  the  recruitment  and  the  selection  of  par- 
ticipating sites.  Could  you  please  describe  what  you  found  in  this 


158 

regard?  Specifically,  how  was  this  process  supposed  to  work,  and 
then  how  did  it,  in  fact,  work? 

Mr.  Herberman.  The  constitution  that  currently  governs  the 
NSABP  is  a  rather  old  document.  It  is  dated  1969  and,  as  best  as 
we  can  determine,  has  had  very  little  updating  since  then.  We  are 
currently  working  on  that  very  matter  and  will  soon  have  a  new 
and  revised  constitution. 

The  description  in  the  constitution,  as  the  original  document 
which  is  now  undergoing  extensive  revision,  was  that  member  in- 
stitutions would  need  to  be  voted  on  by  the  membership  of  the 
NSABP.  For  the  last  number  of  years,  at  least,  this  has  not  been 
the  practice,  but  rather  there  was  an  administrative  mechanism 
within  the  headquarters  operation  for  one  of  the  staff  to  collect  all 
of  the  necessary  documents  and  to  essentially  decide  whether  all 
the  documents  were  in  place  and,  if  so,  to  approve  an  investigator 
or  even  an  institution  for  membership  in  the  NSABP. 

Mr.  DiNGELL.  Now,  Dr.  Herberman,  what  is  your  own  view  of  the 
effect  that  this  violation  of  the  NSABP's  own  constitution  had  on 
the  selection  of  sites  and  their  ability  to  produce  verifiable  data? 

Mr.  Herberman.  Well,  the  NSABP  has  grown  to  be  a  very  large 
and  complex  organization.  It  has  almost  500  sites  which  vary  in 
their  nature  and  their  quality.  I  believe  that  processes  need  to  be 
in  place  to  ensure  the  training  and  the  quality  of  each  of  the  insti- 
tutions that  participate  and  procedures  are  now  being  put  into 
place  to  be  sure  that  the  smaller  institutions  and  the  ones  that  are 
likely  to  accrue  small  numbers  of  patients  will  affiliate  themselves 
with  larger  institutions  in  their  region  so  that  there  can  be  a  direct 
help  to  be  sure  that  the  proper  procedures  are  always  carried  out. 

Mr.  DiNGELL.  Now,  Dr.  Herberman,  can  you  tell  us  what  you 
have  learned  about  the  methods  by  which  NSABP  reimbursed  its 
sites  for  patient  recruitment?  Specifically,  were  the  majority  of  the 
sites  paid  for  accrual  patient  by  patient? 

Mr.  Herberman.  There  have  been  a  variety  of  mechanisms,  Mr. 
Chairman,  for  reimbursing  institutions  that  participate  in  the  clini- 
cal trials.  There  currently  are  11  institutions  that  receive  grants  di- 
rectly from  the  National  Cancer  Institute  for  their  participation  in 
NSABP  clinical  trials. 

The  much  more  common  mechanism  at  the  moment  is  the  dis- 
bursement of  money  through  purchase  service  agreements  that  is 
administered  by  the  headquarters  at  the  University  of  Pittsburgh. 
For  the  purchase  service  agreements,  the  mechanism  essentially  is 
a  per  capita  payment  for  each  participant  entering  onto  a  clinical 
trial. 

Mr.  DiNGELL.  Now,  Dr.  Herberman,  is  it  not  also  true  that  for 
those  sites  payments  were  routinely  made  before  eligibility  for  the 
patient  had  been  confirmed  and  long  before  the  patient  entered  fol- 
low-up? 

Mr.  Herberman.  Well,  sir,  my  understanding  has  been  that  the 
practice  is  that  a  trigger  for  payment  for  a  participant  would  occur 
at  the  time  of  randomization.  A  patient  would  not  be  randomized 
until  checks  for  eligibility  had  been  completed.  But  if  there  subse- 
quently, after  randomization,  was  a  determination  of  ineligibility, 
there  was  not  a  mechanism  in  place  to  recover  such  funds.  There 
also  was  not  a  mechanism  for  adjusting  the  funds  relating  to  the 


159 

extent  or  the  quality  of  the  follow-up.  The  payment  was  made  at 
the  beginning,  with  the  presumption  being  that  this  was  funding 
for  the  entire  process,  the  entry  and  the  follow-up  of  each  partici- 
pant. 

Mr.  DiNGELL.  Two  questions,  then.  Did  this  contribute  to  eligi- 
bility discrepancies?  And  did  it  contribute  to  follow-up  delin- 
quencies? 

Mr.  Herberman.  It  is  hard  to  determine  an  answer  to  that,  Mr. 
Chairman.  I  believe  that  the  very  vast  majority  of  the  participating 
institutions  have  been  extremely  conscientious  in  carrying  out  all 
aspects  of  the  clinical  trials  that  they  participate  in. 

It  is  also  important  to  note  that  the  amount  of  funding  that  was 
coming  from  the  Federal  Government  did  not  provide  full  funding 
for  all  of  the  aspects  of  the  clinical  trials  that  institutions  partici- 
pated in.  I  am  convinced  that  the  primary  motive  for  institutions 
and  the  physicians  associated  with  them  to  participate  was  their 
enthusiasm  about  the  important  work  that  was  being  carried  out 
and  not  directly  linked  to  the  payment  mechanism. 

Mr.  DiNGELL.  Now,  Dr.  Detre,  did  NSABP  ever  attempt  to  recap- 
ture funds  for  patients  ultimately  proven  to  be  ineligible  or  un- 
available for  follow-up? 

Mr.  Detre.  Not  to  the  best  of  my  knowledge,  Mr.  Chairman,  but 
I  may  be  in  error. 

Mr.  DiNGELL.  Could  you  give  us — could  you  tell  us  why? 

Mr.  Herberman.  Mr.  Chairman,  if  you  would  permit  me,  I  think 
I  might  answer  that  question.  This  came  up  for  some  discussion 
when  the  National  Cancer  Institute  officials  visited  the  University 
of  Pittsburgh  last  month. 

What  was  pointed  out  was  that,  because  only  partial  reimburse- 
ment for  the  total  costs  of  the  trials  were  being  performed,  there 
was  a  general  feeling  that  the  amount  of  money  that  was  being  dis- 
bursed was  still  less  than  the  total  cost  that  an  institution  would 
have,  particularly  because  the  proportion  of  ineligible  patients  at 
any  given  institution  has  tended  to  be  relatively  low. 

Mr.  DiNGELL.  Thank  you,  doctor. 

The  Chair  notes  that  I  have  used  about  all  the  time  that  I  should 
at  this  particular  time  so  the  Chair  is  going  to  recognize  my  good 
friend  from  Colorado,  Mr.  Schaefer. 

Mr.  Schaefer.  Thank  you,  Mr.  Chairman. 

I  would  just  like  to,  at  the  outset,  reflect  what  the  chairman  stat- 
ed to  you  gentlemen  about  the  cooperation  with  our  subcommittee 
stafY  in  trying  to  find  all  the  answers  that  we  and  the  American 
public  really  needs  to  know  on  this  matter. 

Earlier  this  week.  Dr.  O'Connor,  the  NCI  announced  it  was  open- 
ing competition  for  the  management  of  NSABP.  Is  the  University 
of  Pittsburgh  going  to  compete  in  this?  Up  to  this  point  it  had  just 
been  a  given,  as  I  understand  it. 

Mr.  O'Connor.  We  certainly  do  intend  to  compete.  Congressman 
Schaefer. 

Mr.  Schaefer.  Now,  if  you  do  compete  in  this,  what  specific  ap- 
proach would  you  take  that  differs  from  the  past  management  of 
NSABP? 

Mr.  O'Connor.  I  think  Dr.  Herberman  will  be  in  a  better  posi- 
tion to  fill  in  some  of  those  details,  Congressman,  but  I  will  say 


160 

that  we  have  aggressively  pursued  an  alteration  of  the  organization 
so  that  it  will  be  both  more  effective  in  monitoring  and  in  commu- 
nicating when  that  needs  to  happen.  But  I  think  Dr.  Herberman 
is  probably  in  a  better  position. 

Mr.  SCHAEFER.  Doctor,  I  know  both  of  you  have  mentioned 
changes  in  your  testimony,  but  do  you  want  to  amplify  a  little 
about  it? 

Mr.  Herberman.  Yes.  Thank  you  for  the  opportunity  to  respond, 
Congressman  Schaefer. 

As  I  briefly  described  in  my  testimony,  we  have  very  rapidly  put 
into  place  an  extensive  series  of  corrective  steps  and  I  believe  im- 
portant improvements  in  the  way  that  the  NSABP  will  operate.  Be- 
cause of  this  intense  focus  on  these  problems  and  giving  virtually 
full-time  dedication  not  only  on  my  part  and  Dr.  Trump's  part  and 
several  other  staff  members,  I  believe  that  we  are  now  uniquely 
suited  to  be  able  to  stabilize  the  group  and  to  keep  its  important 
programs  on  track. 

We  certainly  intend  to  continue  this  progress  and  particularly 
with  the  development  of  these  innovative  data  management  and 
quality  assurance  programs.  We  believe  that  this  is  the  best  pros- 
pect for  the  NSABP  to  function  at  the  highest  possible  level. 

Mr.  Schaefer.  It  seems  to  me  that  in  the  past,  with  the  NCI 
automatically  having  the  University  of  Pittsburgh  do  it,  there 
might  have  been  some  complacency  out  there  and  maybe  this  con- 
tributed to  what  occurred.  I  applaud  you  for  taking  some  new 
steps. 

What,  may  I  ask,  would  Dr.  Fisher's  role  play  if  the  University 
of  Pittsburgh  were  to  get  this  particular  grant? 

Mr.  Herberman.  Congressman  Schaefer,  the  one  thing  that  is 
clear,  I  believe,  is  that  there  is  no  plan  for  Dr.  Fisher  to  resume 
administrative  responsibilities  for  the  NSABP  or  to  have  direct-line 
authority  for  any  aspects  of  the  program. 

Mr.  Schaefer.  Do  the  rest  of  you  gentlemen  concur  with  this? 

Mr.  O'Connor.  That  is  correct,  Mr.  Schaefer.  Dr.  Fisher  has  done 
some  heroic  research  in  the  past  and  will  probably  continue  to  be 
able  to  do  that,  but  he  will  not  have  administrative  responsibility 
in  NSABP. 

Mr.  Schaefer.  You  stated,  and  I  find  it  reassuring,  that 
NSABP's  research  findings  continue  to  be  sound,  and  charges  of  de- 
ficient administration  are  not  adequately  answered  by  merely  as- 
serting that  the  research  remains  valid.  I  gather  that  then  you 
would  dispute  those  who  characterize  the  problems  at  NSABP  as 
trivial  or  nonevents? 

Mr.  O'Connor.  Congressman,  I  don't  think  that  falsification  of 
anything  is  ever  acceptable  and  particularly  when  it  deals  with  the 
public  health. 

Mr.  Schaefer.  So  it  would  not  be  trivial? 

Mr.  O'Connor.  It  is  not  trivial,  sir. 

Mr.  Schaefer.  Thank  you. 

Mr.  Herberman,  I  am  encouraged  in  your  testimony  concerning 
the  steps  you  are  taking  to  improve  the  quality  control  system  of 
NSABP.  It  is,  of  course,  prospective  in  nature.  What  plans  do  you 
have  to  address  the  backlog  of  audit  reports  and  ensure  that  the 
information  currently  in  NSABP's  possession  is  accurate? 


161 

Mr.  Herberman.  Congressman,  this  is  a  matter  of  great  concern 
to  us.  Verification  and  assurance  of  the  quality  of  the  data,  I  be- 
lieve, is  of  primary  concern.  We  are  working  assiduously  to  develop 
an  audit  schedule  in  which  all  of  the  institutions  that  had  not  been 
audited  during  the  requisite  3-year  period  will  be  audited  within 
the  very  near  future. 

In  addition,  all  of  the  institutions  in  which  we  have  detected 
problems  in  previous  audits  will  be  given  the  highest  priority  for 
a  reaudit  and  more  attention.  In  order  to  be  sure  that  this  process 
moves  as  expeditiously  as  possible  and  to  catch  up,  we  have  been 
making  arrangements  with  a  contractor  organization  with  experi- 
ence in  clinical  trials  related  to  cancer  to  help  us  with  this  matter, 
at  least  until  we  can  catch  up  in  the  backlog. 

Mr.  SCHAEFER.  Two  questions.  How  many  of  these  programs 
have  you  identified  as  being  problems?  And  have  you  any  idea 
what  this  is  going  to  cost? 

Mr.  Herberman.  One  of  the  things  that  we  commissioned  shortly 
after  I  took  on  responsibility  for  the  NSABP  was  to  go  back  over 
the  last  4  years  of  all  the  audit  reports.  This  was  over  120  audits. 
Among  those  we  have  determined  there  are  about  11  that  had  sig- 
nificant problems  that  might  affect  eligibility  or  have  important  im- 
pact on  the  clinical  trials.  These  will  be  the  ones  we  will  focus  on 
particularly. 

Mr.  Schaefer.  That  is  a  pretty  high  percent.  We  are  talking  9, 
10  percent. 

Mr.  Herberman.  It  was  about  10  percent.  These  are  serious  con- 
cerns, and  we  will  deal  with  these  expeditiously. 

Mr.  Schaefer.  Again,  you  don't  have  any  idea  of  what  the  cost 
is  going  to  be  involved  in  this?  You  may  not  have  at  this  point,  and 
I  understand  that. 

Mr.  Herberman.  I  really  don't  have  figures  on  the  costs  at  my 
fingertips. 

Mr.  Schaefer.  And  I  understand  that. 

You  are  the  interim  chairman  of  NSABP.  What  is  the  time  frame 
on  the  permanent  chairman?  Will  that  be  this  fall  sometime? 

Mr.  O'Connor.  Congressman  Schaefer,  if  I  may,  we  have  just  es- 
tablished a  search  committee  of  approximately  five  people,  and  I 
am  going  to  chair  that  search,  and  we  hope  to  have  the  individual 
identified  by  late  summer,  early  fall. 

Mr.  Schaefer.  Good.  Dr.  Detre,  do  you  believe  the  peer  review 
system  is  adequate  when  it  comes  to  administration  oversight? 

Mr.  Detre.  Would  you  repeat  the  question.  Congressman  Schae- 
fer? 

Mr.  Schaefer.  I  would  be  happy  to.  Do  you  believe  that  a  peer 
review  system  is  adequate  when  it  comes  to  administration  over- 
sight? 

Mr.  Detre.  I  don't  believe  so.  Congressman  Schaefer.  I  believe 
that  there  must  be  some  additional  institutionally  based  mecha- 
nism to  guarantee  that  the  administration  is  adequate  for  the  task 
at  hand,  particularly  in  such  large-scale  clinical  trials  as  the 
NSABP  which  over  the  years  literally  included  tens  of  thousands 
of  patients  at  400  or  500  different  sites. 


162 

Mr.  SCHAEFER.  In  advocating  the  guidelines  when  it  comes  to  ac- 
cepting philanthropic  funds  from  pharmaceutical  companies,  are 
you  advocating  setting  up  Federal  guidelines  for  this? 

Mr.  Detre.  Mr.  Chairman,  our  conflict  of  interest  guidelines  are 
in  place  at  the  University  of  Pittsburgh.  At  this  point — and  that  I 
believe  is  the  national  standard — we  require  our  faculty  to  report 
any  funds  that  come  from  pharmaceutical  companies. 

Mr.  SCHAEFER.  Mr.  Chairman,  I  would  yield  back. 

Mr.  Brown  [presiding].  Thank  you,  Mr.  Schaefer. 

Dr.  Herberman,  we  have  reviewed  your  May  12th  of  this  year 
draft  report  of  your  review  of  NSABP  recent  audits  for  several 
dozen  sites  with  major  discrepancies.  There  was  no  indication  that 
those  discrepancies  had  been  resolved  or  that  the  potential  irreg- 
ularities further  examined.  How  did  this  occur?  Why  was  this  oc- 
curring at  NSABP? 

Mr.  Herberman.  I  think  that  is  an  important  question.  Con- 
gressman Brown.  I  really  don't  have  a  complete  answer  to  what  the 
reason  for  these  lapses  might  have  been.  We  are  very  concerned 
about  it,  and  I  can  assure  you  that  now  that  I  am  aware  that 
these — some  of  these  reporting  loops  are  open,  we  are  taking  steps 
to  immediately  close  them. 

Mr.  Brown.  What  do  you  intend  to  do?  What  are  you  going  to 
do  to  follow  up  on  these  reports? 

Mr.  Herberman.  Well,  because  we  were  not  entirely  certain 
which  of  some  of  these  reports  had  been  communicated  to  the  NCI, 
we  have  sent  all  of  them  to  the  National  Cancer  Institute  so  they 
have  been  fully  informed. 

In  addition  to  that,  we  are  in  the  process  of  notifying  each  of  the 
principal  investigators  related  to  these  institutions.  It  is,  frankly, 
difficult  for  us  to  determine  from  the  files  which  principal  inves- 
tigators were  informed  and  which  were  not  informed  about  the 
problems.  And  to  ensure  that  everyone  who  needs  to  know  is  in- 
formed, we  will  inform  all  of  them. 

Mr.  Brown.  Why  weren't  these  principal  investigators  informed? 

Mr.  Herberman.  Again,  Congressman  Brown,  it  is  not  clear  to 
me  what  was  the  basis  for  the  lapses  in  the  past.  I,  frankly,  have 
focused  my  attention  not  so  much  on  determining  the  why  but  the 
nature  of  the  problem  itself  and  what  needed  to  be  done  for  correc- 
tive action,  and  this  is  what  I  believe  we  have  done  rather  thor- 
oughly in  the  last  10  weeks. 

Mr.  Brown.  NSABP's  own  audit  report  cites  the  possibility  that 
patients  have  been  given  incorrect  or  inappropriate  treatments  for 
medical  conditions  or  their  care  has  otherwise  been  altered  or  com- 
promised. What  responsibility  does  NSABP  have  to  look  into  the 
well-being  of  these  women? 

Mr.  Herberman.  Well,  Congressman  Brown,  this  is  an  issue  of 
greatest  concern  to  us.  Any  actions  or  inactions  that  would  affect 
the  welfare  of  patients  is,  of  course,  of  first  priority  and  concern. 
It  is  difficult  in  many  cases  well  after  the  fact  when  an  audit  is 
performed,  which  is  often  2  or  more  years  after  a  patient  has  been 
treated,  to  take  a  really  effective  corrective  action  for  that  particu- 
lar woman.  This  is  one  of  the  reasons  why  we  are  putting  this  new 
system  in  place,  so  that  we  can  get  immediate,  real-time  assess- 


163 

ment  of  problems  and  correct  them  while  the  woman  is  still  under 
treatment  so  the  appropriate  treatments  can  be  provided. 

Mr.  Brown.  Dr.  Detre,  do  you  have  anything  to  add  to  that? 

Mr.  Detre.  I  am  not,  of  course,  an  oncologist,  Mr.  Chairman, 
Congressman  Brown.  I  am  just  an  ordinary  physician  who  is  a 
neuropsychiatrist  by  training. 

I  would  say  that  in  those  instances  that  the  questions  about  eli- 
gibility for  trial  for  inappropriateness  of  treatment,  NSABP  under 
a  new  organization  will  provide  for  the  reexamination  of  these 
women  to  provide  them  with  the  best  possible  advice. 

I  might  add  that  while  there  may  have  been  problems  on  eligi- 
bility, which  is  inexcusable,  or  treatment,  which  is  inexcusable,  it 
does  not  necessarily  mean  that  there  are  serious  consequences  of 
these  deficiencies.  These  can  be  determined  only  by  thorough  exam- 
ination of  the  patients  and  proper  consultation  and  advice  to  them. 

Mr.  Brown.  When  will  you  have  done  that? 

Mr.  Detre.  As  soon  as  all  of  these  problems  are  identified. 

And  that  process  is  ongoing — Dr.  Herberman  probably  will  tell 
you  when  all  these  audits  are  finished.  Individuals  who  if  for  any 
reason  whatsoever  may  not  have  received  proper  care  or  were  en- 
rolled in  trials  for  which  they  were  not  eligible  have  to  be  examined 
by  experts  and  not  on  site  but  independent  experts. 

Mr.  Brown.  Dr.  Herberman,  tell  us,  if  you  would,  if  you  would 
identify  the  sites  which  had  the  most  significant  audit  discrep- 
ancies. Would  you  identify  those  for  us? 

Mr.  Herberman.  Certainly.  I  think  the  sites  that  had  the  most 
significant  problems  in  fact  are  the  ones  that  have  come  to  the  pub- 
lic attention.  In  addition  to  St.  Luc  Hospital  in  Montreal  there  is 
a  second  hospital  in  Montreal,  St.  Mary's,  that  my  understanding 
from  Dr.  Broder  there  is  a  determination  of  some  deliberate  alter- 
ation which,  again,  is  of  grave  concern  to  us,  particularly  as  it  has 
occurred  in  the  prevention  trial. 

Beyond  that,  the  institution  where  there  have  been,  I  believe,  the 
most  serious  concerns  or  allegations  brought  forward  has  been  at 
Memorial  Cancer  Research  Foundation  in  Los  Angeles.  In  addition, 
there  have  been  a  few  other  sites  in  which  there  have  been  mul- 
tiple instances  of  what  I  would  characterize  as  sloppiness  in  the 
handling  of  the  records  and  the  clinical  trials  data,  and  for  those 
this  would  include  particularly  LSU  and  Tulane  in  New  Orleans 
and  South  Nassau  Communities  Hospital  in  Long  Island. 

Mr.  Brown.  The  Los  Angeles  site — apparently,  there  was  an 
unmailed  audit  report.  Can  you  tell  us  about  that,  the  United  Me- 
morial Cancer  Foundation? 

Mr.  Herberman.  We  first  learned  about  the  issue  at  Memorial 
in  Los  Angeles  after  it  was  reported  in  the  newspaper  and  when 
Dr.  Plotkin,  the  principal  investigator  there,  requested  the  Na- 
tional Cancer  Institute  to  do  an  audit.  I  spoke  immediately  both  be- 
fore the  audit  and  while  the  audit  was  going  on  with  NCI  officials 
and  determined  that  there  were  serious  enough  problems  to  place 
the  principal  investigator.  Dr.  Plotkin,  on — suspend  him  from  his 
participation  in  the  clinical  trials. 

Why  this  prior  audit  report  which  described  a  number  of  discrep- 
ancies in  1990  was  not  mailed  is  very  difficult  to  determine.  As 
best  as  I  can  surmise,  the  intention  was  to  perform  a  reaudit  and 


164 

to  provide  that  letter  about  the  prior  problems  to  Dr.  Plotkin  at 
that  time,  but  that  reaudit  was  not  performed. 

Mr.  Brown.  You  had  earlier  said  there  were  11  sites.  You  men- 
tioned, I  believe,  6.  You  mentioned  two  in  Montreal,  two  in  Louisi- 
ana, one  on  Long  Island  and  the  Los  Angeles  site.  What  are  the 
other  five? 

Mr.  Herberman.  I  don't  have  the  list  of  the  others  in  front  of  me, 
but  there  are  several  others.  We  could  provide  this  to  the  commit- 
tee almost  immediately. 

Mr.  Brown.  Would  you  please  submit  that  to  us?  Is  one  of  those 
Pittsburgh? 
Mr.  Herberman.  No,  sir. 

Mr.  Brown.  What  is  the  nature  of  the  most  serious  discrepancies 
that  you  found  in  the  audit  reports?  Tell  me  a  little  bit  about  the 
nature  of  them. 

Mr.  Herberman.  Well,  the  type  of  discrepancies  or  problems 
vary  rather  widely.  The  most  serious  one  I  would  characterize  re- 
lates to  information  that  would  affect  eligibility  of  patients  entering 
onto  a  trial. 

A  second  area  of  considerable  concern  has  been  the  documenta- 
tion of  the  informed  consent  and  exactly  when  the  informed  con- 
sent was  administered  and  signed  by  the  patient. 

In  addition  to  that,  there  have  been  some  questions  or  possible 
errors  related  to  laboratory  values  of  patients  and  some  other  is- 
sues about  follow-up,  but  most  of  it,  I  would  say,  was  in  the  area 
of  eligibility  and  consenting. 

Mr.  Brown.  Dr.  O'Connor,  for  a  moment,  you  had  stated  in  your 
opening  statement,  "I  accept  responsibility  for  past  administrative 
shortcomings  and  deficiencies  of  the  NSABP  project,  which  is 
headquartered  at  the  University."  Tell  the  subcommittee  exactly 
what  you  mean  by  that,  "accepting  responsibility." 

Mr.  O'Connor.  I  will  be  happy  to  do  so.  Congressman  Brown. 
I  accept  the  responsibility  of  putting  together  an  administrative 
team  with  Dr.  Detre  and  Dr.  Herberman  which  will  review  the  ad- 
ministration of  the  NSABP  grant  and  bring  it  up  to  an  administra- 
tive quality  that  is  demanded  by  the  kind  of  work  that  it  under- 
takes. 

Mr.  Brown.  The  situation  is  going  to  be  costly  in  at  least  three 
different  ways.  One  is  the  cost  to  the  government  for  investigating 
and  auditing  this  whole  situation;  second  is  the  cost  to  the  Univer- 
sity for  conducting  its  various  reviews  and  inquiries,  and  your  com- 
ing here  and  all  that;  and  third  is  the  cost  of  recruiting  patients 
whose  data  was  found,  for  a  variety  of  reasons,  to  be  unusable. 

Does  Pittsburgh  intend  to  reimburse  the  Federal  Government  for 
the  cost  incurred  in  this  whole  investigation  of  this  matter? 

Mr.  O'Connor.  It  certainly  is  a  point  that  is  under  discussion, 
Congressman  Brown,  and  I  think  it  will  continue  to  be  under  dis- 
cussion. 

Mr.  Brown.  Under  discussion  among  whom? 
Mr.  O'Connor.  Well,  it  certainly  has  been  a  discussion  with  NCI. 
Mr.  Brown.  You  will  make  the  final  decision,  is  my  understand- 
ing, at  the  University  of  Pittsburgh  on  whether  or  not  the  Univer- 
sity agrees  without  any  request  or  action  from  us,  from  the  Federal 


165 

Government,  on  reimbursement.  What  are  your  thoughts  on  that 
today? 

Mr.  O'Connor.  That  I  would  Hke  to  keep  the  discussion  going, 
sir. 

Mr.  Brown.  You  would  like  to  keep  the  discussion  going. 

What  is  your  personal — if  you  had  to  make  a  recommendation  to 
your — since  you  are  making  the  decision,  if  you  had  to  make  the 
recommendation  to  your  board  of  trustees  today,  would  you  rec- 
ommend a  specific  amount  that  you  reimburse  the  government, 
taxpayers,  anything,  that  you  reimburse  the  full  amount? 

Mr.  O'Connor.  Congressman  Brown,  I  don't  have  a  specific  fig- 
ure in  my  head  at  this  point.  That  is  why  I  would  like  to  keep  the 
conversation  going,  so  that  I  can 

Mr.  Brown.  Do  you  think  you  owe  us  something  back  in  dollar 
amounts — not  specific  dollar  amounts,  but  do  you  think  you  owe  a 
dollar  amount  to  us,  back? 

Mr.  O'Connor.  Congressman,  I  need  to  examine  that  very  care- 
fully, very  carefully. 

Mr.  Brown.  You  are  in  charge,  right? 

Mr.  O'Connor.  That  is  correct. 

Mr.  Brown.  Can  you  assure  the  subcommittee  as  a  matter  of  pol- 
icy that  Pittsburgh  will  characterize  and  categorize  all  the  costs  as- 
sociated with  this  situation  as  unallowable  for  Federal  reimburse- 
ment? 

Mr.  O'Connor.  Excuse  me,  I  missed  the  beginning  part  of  the 
question. 

Mr.  Brown.  Can  you  assure  the  subcommittee  that  as  a  matter 
of  policy  that  Pittsburgh  will  characterize  and  categorize  all  its 
costs  associated  with  this  situation  as  unallowable  for  Federal  re- 
imbursement? In  other  words,  the  costs  that  you  are  bearing,  you 
will — the  law  firms  and  whomever  you  may  have  retained  or  hired 
or  expended  moneys  upon,  that  you  will  not  ask  any  of  that  for 
Federal  reimbursement? 

Mr.  O'Connor.  That  is  correct,  sir. 

Mr.  Brown.  OK.  Does  the  University  of  Pittsburgh  plan  to  reim- 
burse the  Federal  Government  for  costs  associated  with  generating 
significant  amounts  of  unusable  data?  Putting  aside  the  series  of 
questions  a  moment  ago,  do  you  plan  to  reimburse  the  government 
for  generating  that  data  that  was  unusable?  Should  taxpayers  pay 
for  that? 

Mr.  O'Connor.  We  have  not  come  to  a  conclusion  on  that  yet, 
Congressman  Brown. 

Mr.  Brown.  Again,  back  to  the  questions  before,  what  is  your 
thinking  as  the  person  in  charge? 

Mr.  O'Connor.  Sir,  I  think  there  are  multiple  costs  involved;  and 
if  there  are  legitimate  costs  that  we  should  reimburse,  then  the 
University's  position  is  that  it  will  reimburse. 

Mr.  Brown.  What  are  legitimate  costs?  Give  me  some  examples 
of  what  you  would  consider  legitimate  costs  that  you  should  reim- 
burse for. 

Mr.  O'Connor.  I  don't  have  one  off  the  top  of  my  head,  Congress- 
man. 

Mr.  Brown.  Give  me  costs  that  you  shouldn't  reimburse  for. 

Mr.  O'Connor.  That  we  should  not  reimburse 


166 

Mr.  Brown.  The  government  for.  Since  you  can't  come  up  with 
any  costs  that  you  should  reimburse  us  for,  are  there  any  that  you 
shouldn't  reimburse  us  for? 

Mr.  O'Connor.  There  may  be  costs  that  the  Federal  Government 
should  be  reimbursed  for,  and  as  I  said,  the  University  will  do  that, 
but  I  don't  have  a  compilation  of  those  costs  in  front  of  me  right 
now,  sir.  I  will  be  happy  to  attempt  to  provide  the  committee  with 
such. 

Mr.  Brown.  What  is  your  role — what  is  your  view.  Dr.  O'Connor, 
about  the  role  of  the  University  in  overseeing  NSABP  with  respect 
to  the  follow-up  of  the  fraudulent  activities  of  St.  Luc  in  Montreal? 

Mr.  O'Connor.  I  think  it  is  a  very  important  role,  Congressman, 
and  I  think  we  intend  to  take  it  very  seriously,  as  Dr.  Herberman 
has  pointed  out. 

Mr.  Brown.  Did  the  University  take  any  steps  to  ensure  that  Dr. 
Fisher  and  his  colleagues  publish  any  reanalysis  of  the  data  in  a 
timely  manner? 

Mr.  O'Connor.  We  have  requested  that  Dr.  Fisher  publish  such 
materials. 

Mr.  Brown.  Prior  to  the  public  revelation  of  the  fraud,  did  you 
ever  take  any  steps  to  ensure  that  he  published  a  reanalysis  of  the 
data? 

Mr.  O'Connor.  Do  you  mind  if  I  ask  Dr.  Detre  some  information 
on  that? 

Mr.  Detre.  Congressman  Brown,  the  University,  sometime  I  be- 
lieve in  1990,  created  a  new  office  to  investigate  scientific  integrity 
precisely  because  Mr.  Dingell's  committee  has  been  critical  of  the 
quality  of  examinations  we  have  done  at  the  University.  In  that 
process — if  you  don't  mind,  I  would  like  to  describe  the  structure 
to  you  just  in  a  sentence  or  two. 

In  this  new  office — it  reports  directly  to  the  chancellor  of  the  uni- 
versity via  university  counsel — the  provost  and  the  senior  vice 
chancellor  for  health  sciences  are  notified  only  when  action  has  to 
be  taken. 

In  the  case  of  Dr.  Poisson  in  Montreal,  I  have  learned  just  a  few 
weeks  ago  that  our  offiice  notified  the  dean  of  the  school  of  medicine 
that  ORI  has  completed  its  investigation  and  instructed  NSABP  to 
do  an  analysis  and  publish  the  information.  I  was  not  notified 
about  that.  Congressman  Brown,  and  maybe  this  degree  of  inde- 
pendence that  the  office  currently  has,  which  was  set  up  for  the 
protection  of  the  university,  has  gone  beyond  its  usefulness. 

Mr.  Brown.  Dr.  Detre,  in  your  prepared  statement,  you  spoke 
about  the  culture  of  deference. 

Mr.  Detre.  Yes,  sir. 

Mr.  Brown.  Culture  of  deference  in  academic  settings  toward  a 
university  senior  scientist,  something  that  obviously — I  would 
think  is  not  unique  to  the  University  of  Pittsburgh  certainly.  Did 
that  culture  of  deference  at  Pittsburgh  toward  Dr.  Fisher,  did  that 
contribute  to  the  university's  failure  of  oversight? 

Mr.  Detre.  I  believe  it  contributes  to  any  university's  failure  be- 
cause we  don't  have  a  mechanism  in  place  to  truly  supervise  senior 
faculty.  Our  expectation.  Congressman  Brown,  is  that  if  there  are 
problems,  they  will  be  reported  by  the  senior  faculty  member  to  the 


167 

chairman  of  the  department  and,  through  him,  to  the  dean;  but 
clearly,  this  mechanism  alone  is  insufficient. 

Mr.  Brown.  You  told  the  subcommittee  staff  in  an  informal  sur- 
vey that  90  percent  of  Pittsburgh's  academic  peers  treat  senior  sci- 
entists in  a  sort  of  similar  hands-off,  detached  fashion  in  a  sense. 
Is  this,  in  fact,  a  problem  throughout  the  University? 

Mr.  Detre.  Congressman  Brown,  I  think  what  I  said  to  the  dis- 
tinguished staff  of  Mr.  Dingell's  committee  is  that  every  university 
has  the  same  tradition  of  deference,  that  we  are  no  exception  to. 

Mr.  Brown.  In  light  of  what  has  happened  at  your  very  fine  uni- 
versity, what  steps  should  the  university  take,  or  what  steps  do 
you  plan  to  take,  to  grapple — to  deal  with  this  whole  cultural  def- 
erence to  assure  accountability  and  to  be  responsive  to  the  public 
trust  when  Federal  dollars  or  any  government  dollars  are  involved? 

Mr.  Detre.  Congressman  Brown,  as  I  earlier  said  to  a  question 
posed  by  Congressman  Schaefer,  I  believe  that  an  external  quality 
assurance  and  auditing  program  is  absolutely  essential  to  guaran- 
tee the  proper  administration  of  these  matters. 

Mr.  Brown.  Is  the  University  of  Pittsburgh  going  to  lead  the 
way? 

This  culture  of  deference  that  you  have  labeled  clearly  can  cause 
potential  problems  in  university  settings  across  the  country.  Do  you 
see  any  role  for  the  University  of  Pittsburgh  to  serve  to  lead  the 
way  in  beginning  to  undo  some  of  that? 

Mr.  Detre.  We  intend  to  be  the  leader  in  this,  though  I  fully  rec- 
ognize. Congressman  Brown,  that  it  will  not  necessarily  win  a  pop- 
ularity contest. 

Mr.  Brown.  Talk  to  me  a  little  about  what  "the  culture  of  def- 
erence" means.  I  understand  what  it  means  exactly  in  this  NSABP 
case,  where  there  wasn't  a  challenge  to  things  he  was  saying,  but 
does  it  include  things  like  these  lavish  conferences  in  Hilton  Head 
and  first  class  airfare  and  even — 

Mr.  Detre.  I  don't  think  that  has  anything  to  do  with  it. 

You  know,  as  distasteful  as  it  may  appear  to  you,  I  don't  believe 
that  is  the  real  problem.  The  real  problem  is  that  when  deficiencies 
are  identified — and  I  would  like  to  remind  you.  Congressman,  that 
actually  it  was  NSABP  that  discovered  the  cheating  at  Montreal, 
not  another  agency;  so  the  difficulties  we  find  ourselves  in — that 
we  have  no  way  of  monitoring  whether  all  necessary  corrective  ac- 
tions have  been  taken  or  not.  This  is  our  major  deficiency. 

Mr.  Brown.  Tell  me  some  specific  examples  of  some  of  the  nega- 
tive outgrowths  of  this  cultural  deference,  how  it  is  manifested  in 
a  way  that  does  not  add  to  public  knowledge,  might  potentially 
abuse  the  public  trust,  is  more  of  a  negative  than  a  positive. 

Mr.  Detre.  Congressman  Brown,  do  you  want  to  see  an  even 
more  vivid  example  than  what  we  are  witnessing  now,  the  reason 
why  we  are  here? 

Mr.  Brown.  Sure. 

Mr.  Detre.  I  think  it  is  a  perfect  example  of  the  difficulties  uni- 
versities find  themselves  in,  because  we  do  not  have  a  university- 
based  but  independent  quality  assurance  and  audit  program  which 
would  help  us  to  identify  problems  and  correct  them. 

Mr.  Brown.  Why  not? 


168 

Mr.  Detre.  It  has  not  been  part  of  our  culture,  Congressman. 
The  society  learns  gradually  from  its  mistakes. 

I  remember  that  15  years  ago  neither  Congress  nor  universities 
had  any  conflict-of-interest  policies.  We  now  have  them.  I  think 
this  is  a  gradual  growing  process.  We  learn  from  our  mistakes,  and 
we  try  to  rectify  them. 

Mr.  Brown.  Dr.  O'Connor,  I  assume  you  are  going  to  accelerate 
some  of  that  learning  process? 

Mr.  O'Connor.  I  certainly  hope  to,  Congressman  Brown. 

Mr.  Brown.  Thank  you,  gentlemen,  for  testifying,  for  being  with 
us  today.  We  will  take  a  short,  15-minute  recess  or  so,  while  the 
chairman  and  the  rest  of  us  vote.  Then  we  will  call  Dr.  Fisher  im- 
mediately upon  returning. 

[Brief  recess.] 

Mr.  Dingell.  The  Chair  advises  the  next  panel  is  composed  of 
Dr.  Bernard  Fisher,  M.D.,  former  chairman.  National  Surgical  Ad- 
juvant Breast  and  Bowel  Project. 

Dr.  Fisher,  welcome  to  the  committee. 

The  Chair  advises  that  all  witnesses  are  sworn  before  the  com- 
mittee. Do  you  have  any  objection  to  being  sworn  in? 

Mr.  Fisher.  No,  sir. 

Mr.  Dingell.  Very  well.  The  Chair  advises  that  you  are,  since 
you  will  be  testifying  under  oath,  entitled  to  be  advised  by  counsel. 
Do  you  so  desire? 

Mr.  Fisher.  Yes,  sir. 

Mr.  Dingell.  Your  counsel  is  seated  next  to  you.  You  are? 

Mr.  Onek.  Mr.  Joseph  Onek,  Mr.  Chairman. 

Mr.  Dingell.  How  do  you  do,  sir.  The  Chair  will  note  for  the 
record  that  you  will  then  be  advising  Dr.  Fisher.  The  Chair  advises 
that  copies  of  the  rules  of  the  subcommittee,  the  committee,  and 
the  House  are  there  at  the  witness  table  to  assist  you  as  you  testify 
before  the  committee. 

If  you  have,  then,  Doctor,  no  objection  to  testifying  under  oath, 
if  you  will  please  rise  and  raise  your  right  hand. 

[Witness  sworn.] 

Mr.  Dingell.  You  may  consider  yourself  then  under  oath,  Doc- 
tor, and  the  Chair  will  recognize  you  for  such  opening  statement 
as  you  choose  to  give. 

TESTIMONY  OF  BERNARD  FISHER,  FORMER  CHAIRMAN,  NA- 
TIONAL SURGICAL  ADJUVANT  BREAST  AND  BOWEL 
PROJECT,  UNIVERSITY  OF  PITTSBURGH,  ACCOMPANIED  BY 
JOSEPH  ONEK,  COUNSEL 

Mr.  Fisher.  Thank  you,  sir.  Mr.  Chairman,  members  of  the  sub- 
committee, I  am  grateful  to  have  the  opportunity  to  be  here  today. 
I  am  Dr.  Bernard  Fisher,  distinguished  service  professor  of  surgery 
at  the  University  of  Pittsburgh.  Over  the  years,  I  have  been  a 
member  of  the  President's  Cancer  Panel,  the  Board  of  Scientific 
Counselors,  and  the  National  Cancer  Advisory  Board  of  the  Na- 
tional Cancer  Institute. 

I  have  passionately  devoted  more  than  35  years  to  the  study  and 
treatment  of  breast  cancer  to  the  exclusion  of  almost  everything 
else  in  my  life.   My  studies  involving  nearly  50,000  women  and 


169 

5,000  health  professionals  at  500  institutions  in  North  America 
have,  I  believe,  revolutionized  the  treatment  of  that  dread  disease. 

As  a  result  of  the  research  by  the  NSABP,  which  I  chaired  for 
27  years,  women  with  breast  cancer  now  have  a  choice  to  save  their 
breasts  rather  than  to  undergo  a  disfiguring  radical  mastectomy. 
Our  work  has  shown  that  chemotherapy  and  tamoxifen  after  sur- 
gery increases  survival. 

We  recently  began  the  study  to  determine  whether  breast  cancer 
can  be  prevented  in  women  at  high  risk.  If  the  findings  from  that 
trial  indicate  that  the  risk  of  breast  cancer  can  be  reduced,  the 
problem  of  breast  cancer  would  be  significantly  diminished. 

The  events  arising  out  of  the  data  falsification  in  Canada  have 
been  tragic  for  me,  my  colleagues,  our  families,  and  for  all  women 
in  this  country.  Women  with  breast  cancer  began  to  doubt  the  ther- 
apy they  had  received.  Those  without  breast  cancer  lost  confidence 
in  the  system  that  they  someday  might  need  to  rely  upon. 

Mr.  Chairman,  I  can't  emphatically  enough  state  that  women 
must  not  become  the  victims  of  these  events.  In  my  statement,  I 
will  address  point  by  point  specific  matters  that  have  arisen  during 
the  past  few  months. 

First,  I  sincerely  share  the  subcommittee's  concern  regarding 
fraud  in  science  and  believe  that  any  deviation  from  scientific  in- 
tegrity is  not  acceptable.  My  whole  scientific  life  has  been  based  on 
that  credo.  I  deeply  regret  that  there  was  data  falsification  by  a 
physician  at  one  of  the  hospitals  participating  in  the  NSABP. 

Second,  despite  the  data  falsification,  women  can  and  must  feel 
secure  that  lumpectomy  following  radiation  therapy  is  as  effective 
a  treatment  as  removal  of  the  breast.  Our  studies,  as  well  as  those 
of  others,  have  consistently  supported  our  findings.  The  NCI,  upon 
recent  review  of  our  results,  reached  the  same  conclusion. 

Third,  there  never  was  any  intent  to  hide  information  regarding 
the  discovery  of  falsified  data  at  St.  Luc  Hospital  in  Montreal,  and 
I  emphasize  that.  There  never  was  any  intent  by  me  or  my  associ- 
ates to  hide  any  information  regarding  the  discovery  of  that  infor- 
mation. 

On  November  14,  1990,  I  was  notified  by  Dr.  Carol  Redmond,  Di- 
rector of  the  NSABP  Biostatistical  Center,  that  data  discrepancies 
found  at  St.  Luc  Hospital  were  being  investigated.  At  that  point, 
no  fraud  had  been  identified. 

In  February  1991,  following  further  investigation  by  the 
Biostatistical  Center,  it  was  found  that  data  falsification  had  oc- 
curred. We  immediately  notified  the  NCI  and  the  investigator.  Dr. 
Roger  Poisson,  was  suspended. 

We  believe  that  the  detection  and  reporting  of  the  St.  Luc  Hos- 
pital fraud  was  carried  out  according  to  the  1988  clinical  trials  co- 
operative group  program  guidelines  which  state  that,  "In  more  seri- 
ous cases,  it  is  the  responsibility  of  each  group  to  define  the  gravity 
and  degree  of  potential  problems  and  to  be  consistent  and  fair  in 
the  actions  and  sanctions  it  applies  when  significant  problems  are 
uncovered."  The  time  spent  by  the  NSABP  investigation  was  used 
to  ensure  that  a  fair  action  was  taken. 

After  we  alerted  NIH,  an  official  investigation  was  begun  by  the 
Office  of  Scientific  Integrity,  OSI.  We  were  embargoed  from  further 
discussions  of  the  matter.   On  several  occasions,  the  data  from 


170 

NSABP  studies  in  which  Dr.  Poisson  participated  were  reanalyzed, 
eliminating  his  patients. 

In  March  of  1992,  the  findings  were  shared  with  members  of  the 
NCI,  OSI,  and  NIH.  These  findings  indicated  that  when  all  data 
from  St.  Luc  Hospital  were  removed  from  the  reanalyses,  the  out- 
comes and  conclusions  of  all  of  our  previously  published  studies 
were  unchanged.  We  had  already  notified  the  NSABP  Executive 
Committee  of  the  Poisson  affair  and  of  the  results  of  our  reanalyses 
in  February  of  1992. 

The  OSI  thorough  investigation  found  falsification  in  99  breast 
cancer  patients  in  22  studies.  These  falsifications  represented  0.3 
percent  of  the  33,885  women  in  our  studies;  98  of  the  99  alterations 
were  related  to  patient  entry  criteria.  In  randomized  studies,  such 
types  of  falsifications  are  unlikely  to  influence  patient  outcome. 

Let  me  emphasize  this  firmly,  if  our  reanalyses  had  produced 
evidence  that  the  conclusions  of  our  studies  were  affected  by  the 
data  alterations,  we  would  have  reported  our  findings  immediately. 
Neither  we,  the  NCI,  the  NIH,  nor  the  OSI  perceived  that  the 
Poisson  falsifications  had  resulted  in  a  public  health  problem.  If 
the  NCI  had  considered  this  to  be  the  case,  they  could  have  issued 
a  clinical  alert. 

Our  plan  was  to  present  our  findings  to  the  scientific  community 
in  a  peer-reviewed  publication  and  to  prepare  a  comprehensive 
technical  report.  We  didn't  realize  that  the  failure  to  publish  our 
findings  immediately  would  be  misinterpreted  by  the  public  as  an 
indication  that  we  were  concealing  information.  Such  a  perception 
resulted  in  the  unjustified  concern  that  women  with  breast  cancer 
were  receiving  inappropriate  therapy. 

We  should  have  been  more  sensitive  to  this  possibility  and  we 
should  have  published  our  reanalyses  more  promptly,  and  I  truly 
apologize  for  that  delay. 

For  30  years,  the  goal  of  the  NSABP  was  to  provide  better  infor- 
mation to  patients  and  their  physicians.  The  suggestion  that  we 
suppressed  information  is  painful.  We  never  attempted  to  hide  any 
information.  There  could  have  been  no  conceivable  reason  for  us  to 
do  so. 

Fourth,  concern  has  been  raised  regarding  inclusion  of  data  from 
St.  Luc  Hospital  in  NSABP  reports  published  after  February  1991, 
when  the  Poisson  fraud  was  found.  There  are  honest  differences  of 
opinion  among  statisticians  regarding  the  handling  of  falsified  data 
in  large  clinical  trials.  There  are  significant  scientific  reasons  not 
to  exclude  all  such  data. 

Our  statisticians  considered  that  it  was  not  appropriate  to  ex- 
clude all  data  from  those  patients  who  had  a  diagnosis  of  breast 
cancer  and  who  had  been  randomized,  treated,  and  followed  appro- 
priately. Excluding  all  patients  would  have  prevented  identification 
of  toxicities  and  other  adverse  events. 

During  the  OSI  embargo,  we  could  not  exclude  data  without  dis- 
cussing the  findings  with  journals;  and  after  the  embargo  was  lift- 
ed, we  complied  with  the  NCI  request  of  January  1993  that  no  data 
from  St.  Luc  be  included  in  publications  containing  new  data. 

A  fifth  concern  relates  to  the  reporting  of  deaths  from 
endometrial  cancer  in  breast  cancer  patients  treated  with 
tamoxifen.  As  was  mentioned  previously,  there  are  more  than  4 


171 

million  women  using  that  drug.  Clinical  trials  have  demonstrated 
that  the  benefit  from  tamoxifen  is  about  20  times  greater  than  the 
risk  of  getting  endometrial  cancer.  Consequently,  women  with 
breast  cancer  should  continue  to  take  tamoxifen,  although  some  un- 
desirable effects  may  occur. 

In  our  studies,  we  found  that  of  2,693  breast  cancer  patients 
being  treated  with  tamoxifen,  23  developed  endometrial  cancer  and 
4  deaths  occurred.  There  is  no  substance  to  the  suggestion  that  we 
withheld  information  concerning  these  four  deaths. 

It  is  important  to  understand  the  difficulties  involved  in  deter- 
mining the  cause  of  death  in  breast  cancer  patients  with 
endometrial  cancer.  When  a  death  occurs  in  a  woman  who  had  both 
breast  cancer  and  endometrial  cancer,  it  is  extremely  difficult  to  be 
sure  which  cancer  caused  the  death.  It  cannot  be  assumed  that  the 
death  occurred  as  a  result  of  the  endometrial  cancer;  she  may  have 
died  of  breast  cancer.  Only  by  continuing  medical  review  and 
rereview  and  by  obtaining  difficult-to-get  information  can  we  be 
sure  which  cancer  caused  the  death.  Such  medical  detective  work 
can  take  a  long  time. 

There  is  often  delay  in  obtaining  information  about  deaths  be- 
cause patients  move,  go  to  different  hospitals,  change  physicians  or 
because  families  fail  to  notify  physicians  about  a  death.  These  de- 
layed responses  can  result  in  a  delay  in  confirming  the  cause  of 
death.  Death  certificates  can  be  ambiguous  or  inaccurate  and  not 
readily  obtainable.  Autopsies  are  infrequently  performed  and  often 
fail  to  aid  in  determining  the  cause  of  death. 

In  the  fall  of  1993,  we  confirmed  that  there  had  been  deaths  from 
endometrial  cancer  in  tamoxifen  patients  and  reported  this  fact  to 
the  NSABP,  the  NCI,  and  the  drug  manufacturer.  In  retrospect,  it 
might  have  been  possible  to  collect  and  report  information  about 
these  deaths  sooner,  but  there  was  never  any  intent  to  withhold 
any  information. 

Sixth,  concerns  have  been  raised  about  the  NSABP  audit  proce- 
dures. The  NSABP  verifies  and  evaluates  the  quality  of  data  sub- 
mitted by  a  quality  assurance  program  which  has  two  parts.  One 
is  the  on-site  audit  program  in  which  visits  to  participating  institu- 
tions are  made  at  least  once  during  a  3-year  period  by  NSABP  per- 
sonnel. Selected  samples  of  patient  records  are  examined. 

In  the  second  part  of  the  program,  extensive  source  records  from 
all  patients  are  received  and  examined  at  the  NSABP  head- 
quarters. In  1991,  the  reviewers  of  our  grant  application  to  the  NCI 
termed  our  procedures  "exemplary." 

Since  1991,  there  have  been  significant  changes  in  the  workload 
of  the  NSABP.  The  initiation  of  the  breast  cancer  prevention  trial 
has  resulted  in  an  increase  in  the  number  of  patients  being  fol- 
lowed in  NSABP  studies  from  25,000  in  1991  to  41,000  in  1993; 
and  the  number  of  data  forms  processed  expanded  from  225,000  in 
1991  to  413,000  in  1993. 

In  retrospect,  the  administrative  infrastructure  of  the  NSABP 
did  not  keep  pace  with  this  tremendous  growth.  There  have  been 
some  delays  in  our  auditing  and  reporting  functions. 

I  accept  my  share  of  the  responsibility  for  these  administrative 
deficiencies  that  occurred;  I  could  have  been  more  aggressive  in 
seeking  funding  for  additional  administrative  personnel.  In  retro- 


172 

spect,  I  should  have  brought  on  more  executive  administrative  peo- 
ple to  help  manage  the  program,  an  executive  director.  Perhaps  my 
passionate  attention  to  the  science  overshadowed  my  administra- 
tive insight,  and  this  was  a  mistake.  I  should  have  been  firmer 
with  the  personnel  responsible  for  the  audit  program. 

I  believe  that  the  administrative  deficiencies  of  the  NSABP  could 
be  remedied  quickly.  For  this  reason,  I  am  troubled  by  the  pro- 
longed suspension  by  the  NCI  of  all  NSABP  clinical  trials  in 
progress  and  the  postponement  of  the  development  and  start  of 
new  studies.  These  events  could  affect  the  lives  of  thousands  of 
breast  cancer  patients  in  years  to  come.  Clinical  trials  must  be  re- 
stored at  once. 

Women  and  their  doctors  must  realize  that  large  multicenter 
randomized  trials  are  the  best  way  to  obtain  information  for  mak- 
ing treatment  decisions.  The  randomization  of  patients  in  trials 
eliminates  the  chance  of  obtaining  biased  results. 

Clinical  trials  also  provide — and  I  emphasize  this — higher  stand- 
ards of  patient  care.  If  clinical  trials  are  eliminated,  we  have  no 
good  alternatives.  We  cannot  return  to  the  system  where  treatment 
is  based  on  physicians'  intuition. 

Finally,  I  thank  the  NCI  for  the  support  which  made  my  life's 
work  possible.  For  25  years,  NSABP's  relationship  with  officials  of 
the  NCI  was  based  upon  mutual  respect  and  cooperation.  Members 
of  the  NCI  have  been  involved  in  every  aspect  of  our  efforts.  They 
have  continuously  been  aware  of  and  have  participated  in  our  suc- 
cesses and  were  intimately  involved  with  the  decision-making  proc- 
ess of  our  group.  This  was  truly  a  cooperative  agreement  in  name 
and  in  fact. 

It  is  necessary  for  the  good  of  the  women  in  this  country  that  we 
now  look  to  the  future.  Within  the  last  6  months,  I  have  formulated 
a  strategic  plan  for  a  new  generation  of  clinical  trials,  which  I 
hoped  would  be  my  legacy,  which  could  significantly  alter  the  fu- 
ture treatment  of  breast  cancer  patients. 

One  such  study  evaluates  the  use  of  preoperative  therapy,  and 
if  the  results  indicate,  primary  surgical  treatment  for  breast  cancer 
will  become  obsolete.  Information  from  another  study  could  more 
clearly  define  a  patient's  risk  for  developing  a  treatment  failure 
and  consequently  identify  which  patients  should  or  should  not  re- 
ceive a  particular  therapy.  Other  studies  by  us  are  evaluating  new 
and  exciting  therapeutic  agents  that  can  be  better  than  those  cur- 
rently used. 

For  progress  to  be  made  in  breast  cancer  treatment,  the  public's 
faith  in  clinical  trials  must  not  be  diminished  by  these  current 
events  or  any  other. 

In  conclusion,  I  emphasize  that  any  deviation  from  scientific  in- 
tegrity is  unacceptable.  While  fraudulent  data  were  submitted  by 
a  contributing  investigator,  the  NSABP  studies  themselves  are  not 
fraudulent.  There  was  never  any  intent  to  hide  information  or  de- 
ceive anybody.  During  the  course  of  all  our  activities,  NCI  and 
Zeneca  were  intimately  involved. 

System  errors  can  and  did  occur  and  must  be  repaired.  I  believe, 
as  was  heard,  improved  technology  will  help.  Above  all,  we  must 
not  allow  these  recent  events  to  deflect  us  from  our  ultimate  goal — 
the  prevention  and  cure  of  breast  cancer  in  women. 


173 

Thank  you,  sir. 

Mr.  DiNGELL.  Thank  you,  Dr.  Fisher.  The  Chair  is  going  to  recog- 
nize himself  first. 

Doctor,  could  you  tell  the  subcommittee  the  importance  of  an 
audit  program  to  a  clinical  trial  such  as  the  one  you  headed  at 
NSABP,  please? 

Mr.  Fisher.  Yes,  sir.  The  purpose  of  an  audit  program  is  to  ver- 
ify the  quality  of  information  that  is  being  obtained  and  is  being 
submitted  to  the  NSABP  Headquarters. 

Mr.  DiNGELL.  Now,  Dr.  Fisher,  during  the  course  of  the  trials 
conducted  at  NSABP,  your  staff  conducted  literally  hundreds  of 
these  audits;  is  that  correct? 

Mr.  Fisher.  Yes,  sir.  There  were  587  audits  conducted  in  four  cy- 
cles. 

Mr.  DiNGELL.  Now,  Doctor,  tell  me  who  is  Dr.  Wickersham  or 
Wickerham? 

Mr.  Fisher.  Dr.  Wickerham  is  the  Deputy  Director  of  the  Oper- 
ations Office. 

Mr.  DiNGELL.  He  is  the  chief  medical  person  in  the  study,  is  that 
right,  and  the  auditors  reported  to  him? 

Mr.  Fisher.  The  audit  program  has  two  parts.  The  audit  pro- 
gram has  a  part  which  is  conducted  by  the  Biostatistical  Center. 
The  Biostatistical  Center  is  the  one  responsible  for  scheduling  au- 
dits, sending  out  people  to  audit  the  program,  to  bring  and  to  ex- 
amine the  things  that  they  do  at  the  site,  and  to  bring  back  to  the 
Headquarters  source  information,  reports  of  x  rays,  all  kinds  of 
things,  laboratory  information,  information  about  treatment,  and  so 
on;  and  then  at  the  Headquarters,  by  the  Biostatistical  Center,  this 
is  all  reviewed  to  make  sure  that  what  was  sent  in  originally  is 
that  which  exists  in  the  source  document. 

Mr.  DiNGELL.  Dr.  Wickerham  told  the  subcommittee  staff  that  he 
routinely  gave  you  copies  of  the  audit  reports  at  the  NSABP  sites; 
is  that  correct? 

Mr.  Fisher.  I  received  audit  reports.  I  cannot  say  with  certainty 
whether  these  were  routine  or  all  audit  reports,  but  I  did  receive 
audit  reports. 

Mr.  DiNGELL.  Now,  Doctor,  the  subcommittee  staff  has  been  re- 
viewing the  audit  reports  for  the  last  month  or  so,  and  it  has  found 
that  in  addition  to  the  St.  Luc  problems  relative  to  fraud,  your 
auditors  uncovered  a  number  of  similar  problems  at  sites  through- 
out the  NSABP. 

For  example,  a  number  of  locations  were  found  to  be  violating 
the  eligibility  criteria.  At  one  site,  %  of  the  patients  enrolled  did 
not  meet  the  eligibility  criteria.  Can  you  tell  us  about  what  you 
knew  about  these  matters  regarding  the  depth  and  the  breadth  of 
eligibility  problems  identified  by  your  auditors? 

Mr.  Fisher.  Mr.  Chairman,  we  recognized  that  there  were  ad- 
ministrative deficiencies  in  the  audit  program,  but  with  respect  to 
any  particular  institution,  we  have  not  had  a  chance  to  review  the 
subcommittee's  investigations  or  reports  or  any  other  recent  analy- 
ses, and  we  would  certainly  like  to  have  the  opportunity  to  do  so 
and  provide  the  information  to  you.  There  may  be  some  misunder- 
standings regarding  clarification  of  ineligibility  and  other  terms 
which  exist. 


174 

Mr.  DiNGELL.  I  am  not  going  to  refer  to  the  specific  sites  unless 
it  appears  to  be  desirable  so  to  do,  but  these  were  audits  which 
were  performed  over  the  years,  clear  back  into  the  1990's,  the  early 
1990's,  and  on  back  even  beyond  that  into  the  1980's.  And  that  was 
at  a  time  when  you  were  in  charge  of  the  program,  and  didn't  they 
give  you  some  awareness  of  the  fact  that  there  were  problems  with 
either  fraud  or  slovenly  work? 

Mr.  Fisher.  Well,  it  was  the  audit  process  which  did  uncover  the 
St.  Luc;  it  was  the  part  of  the  quality  assurance  program  which  un- 
covered the  St.  Luc  falsifications.  We  found  those  falsifications 
through  our  efforts,  and  reported  them,  and  that  is  the  only  fal- 
sification that  has  been 

Mr.  DiNGELL.  Of  course.  Doctor,  these  went  to  eligibility  and 
showed  that  there  were  some  fairly  significant  eligibility  questions. 
For  example,  one  site  had  three-quarters  of  the  participants  ineli- 
gible. 

Mr.  Fisher.  I  am  certainly  unaware  of  that,  sir.  I  really  am  not 
aware  of  it. 

Mr.  DiNGELL.  But  it  was  in  audit  reports  that  came  to  you, 
though. 

Mr.  Fisher.  I  don't,  I  really  don't  remember  seeing  that  report 
at  all. 

Mr.  DiNGELL.  Well,  here  they  are,  and  I  am  just  going  to  lay 
them  out.  South  Nasau  Hospital,  Rush  Presbyterian  Hospital,  St. 
Joseph  Hospital  in  Lancaster,  and  in  the  University  of  Pittsburgh. 
Now,  the  University  of  California  Davis  had  %  of  the  participants 
in  the  study  ineligible. 

Mr.  Fisher.  I  have  never  seen  that. 

Mr.  DiNGELL.  These  were  audits,  these  were  your  audits  in  your 
project. 

Mr.  Fisher.  May  I  make  a  comment  about  eligibility? 

Mr.  DiNGELL.  Sure. 

Mr.  Fisher.  Eligibility  has  been — the  term  "eligibility"  has  been 
used  here  and  elsewhere.  Eligibility  is  not  falsification. 

Mr.  DiNGELL.  We  are  not — I  am  not  making  the  allegation  that 
eligibility  is  a  fraud,  or  fraud  or  similar  question.  It  is,  however, 
a  matter  which  goes  to  the  very  reality  and  scientific  adequacy  of 
the  test,  because  if  you  are  testing  people  or  reporting  on  people 
who  don't  meet  your  eligibility  requirements,  it  tends  to  skew  your 
results.  And  what  I  am  trying  to  find  out  is,  all  of  these  matters 
were  essentially  found  in  audits,  but  we  are  not  able  to  address 
them  here  today  because  of  your  lack  of  familiarity  with  them. 

Mr.  Fisher.  I  certainly  am  not  aware  of  any  institution  where 
there  were  %  of  the  patients  ineligible.  I  should  like  to  have  more 
information  about  that  than  I  have. 

Mr.  DiNGELL.  Well,  we  will  give  it  to  you.  It  is,  however,  I  would 
observe.  Doctor,  in  your  own  audit  reports. 

Now,  here  are  other  examples.  Auditors  turned  up  instances 
where  patients  were  randomized  twice.  What  is  the  result  of  ran- 
domizing a  patient  twice  in  a  study  of  this  kind?  What  does  it  do 
to  the  statistical  validity  of  the  study? 

Mr.  Fisher.  I  can't  answer  that  question. 

Mr.  DiNGELL.  Do  you  know  how  much  double  randomization  was 
occurring  and  what  the  practical  effect  of  it  was? 


175 

Mr.  Fisher.  Sir,  I  don't  know  the  number  of  double 
randomizations,  but  I  must  think  they  were  extremely  few  and  far 
between.  This  has  not  been  brought  to  my  attention  as  being  a 
problem. 

Mr.  DiNGELL.  Well,  your  auditors  also  identified  a  number  of  in- 
formed consent  problems  throughout  the  site — throughout  the  dif- 
ferent sites.  For  example,  no  documentation  of  informed  consent 
obtained  up  to  2  years — obtained  up  to  2  years  post  randomization 
and  so  forth.  Now,  what — first  of  all,  does  this  constitute  a  problem 
in  terms  of  lack  of  adequate  informed  consent  by  the  participants, 
and  if  so,  what  was  done? 

Mr.  Fisher.  Let  me  say  emphatically  that  informed  consent  is  a 
very  important  part  of  what  we  are  doing.  It  always  has  been. 

Mr.  DiNGELL.  It  is  really  an  ethical  question. 

Mr.  Fisher.  Absolutely.  There  is  no  question  about  that.  And  as 
far  as  I  am  concerned,  that  is  something  that  there  can  be  no  ex- 
cuses for.  There  are  certain  situations  where  in  one  of  the  studies, 
for  example,  wherein  formed  consent  may  have  been  obtained  after 
an  operation  was  done  that  is  in  a  particular  study  of  lumpectomy 
where  prerandomization  was  used,  but  in  reference  to  your  com- 
ments about  informed  consent,  I  have  seen  in  some  of  the  audit  re- 
ports that  there  was  this  kind  of  situation,  but  I  have  not  been  fa- 
miliar with  it  as  any  kind  of  a  serious  problem. 

Mr.  DiNGELL.  Well,  your  auditors  found  a  number  of  sites  that 
were  not  maintaining  drug  laws.  Can  you  tell  us  the  importance  of 
the  drug  laws — rather  the  drug  logs  and  what  happened  at  the  lo- 
cations that  were  not  properly  maintaining  these  logs? 

Mr.  Fisher.  Drug  logs  are  also  something  that  is  looked  for  at 
the  site  routinely  to  make  sure  that  the  drugs  that  are  given  to  the 
investigators  are  used  for  the  patients  that  they  are  supposed  to 
be  used  on. 

Mr.  DiNGELL.  Well,  but  here  you  have  another  instance  where 
the  drug  logs  were  not  maintained.  Is  that  important,  or  is  that  not 
important? 

Mr.  Fisher.  As  far  as  I  am  concerned,  it  is  important. 

Mr.  DiNGELL.  Now,  a  number  of  other  locations  had  serious  prob- 
lems with  missing  data.  Were  you  aware  of  this? 

Mr.  Fisher.  I  have  heard  about  that,  particularly  in  certain  insti- 
tutions, and  it  depends  again  on  how  long  ago  the  data  was  col- 
lected. For  example,  at  one  of  the — in  New  Orleans,  for  example, 
where  data  was  collected  in  the  1970's  at  a  large  city  hospital, 
some  of  that  data  now  in  1994  may  be  hard  to  obtain.  I  cannot 
know  more  than  that  about  it,  however. 

Mr.  DiNGELL.  Well,  if  the  failure  to  maintain  proper  logs  and  to 
have  the  data  properly  assembled  is  recent,  is  that  a  more  serious 
problem? 

Mr.  Fisher.  These  things  are  all  problems.  There  is  no  question 
about  that.  And  I  would  certainly  like  to  address  them  after  I  knew 
more  about  the  degree  of  these  problems.  For  example,  I  indicated 
to  you  that  the  NSABP  had  conducted  587  audits  since  1982,  and 
of  those  587  audits,  there  were  only — there  were  major  problems 
identified  in  5.8  percent,  and  some  of  those  problems  deal  with  the 
things  that  you  are  talking  about. 


176 

Mr.  DiNGELL.  You  mean  there  were  problems  identified  in  5.8 
percent  of  the  audits? 

Mr.  Fisher.  Which  were  considered  to  be  serious  enough  to  sus- 
pend these  investigators. 

Mr.  DiNGELL.  Well,  these  involved  some  30  institutions.  Are  you 
able  to  tell  me  that  these  were  trivial  matters  or  that  they  were 
not  important  matters? 

Mr.  Fisher.  No,  sir.  I  in  no  way  make  any  indication  that  these 
are  trivial.  We  do  the  audits  to  determine  these  things.  Otherwise, 
there  would  be  no  point  in  doing  the  audit  program. 

Mr.  DiNGELL.  Well,  I  think  you  raise  an  important  question. 
What  did  you  do  with  the  audits?  The  audits  come  in,  they  said, 
for  example,  there  is  a  problem  with  informed  consent.  They  say 
that  a  number  of  sites  were  not  maintaining  drug  logs.  They  say 
that  there  was  a  serious  problem  with  missing  data.  Did  you  in- 
quire into  these  problems? 

Mr.  Fisher.  The  usual  process  would  be  that  when  this  happens, 
the  medical  auditor,  medical  reviewer,  will  write  a  report,  and  that 
report  will  indicate  to  the  investigator  what  the  problems  are  and 
we  would  expect  them  to  implement  a  plan  of  action  to  tell  us  what 
they  are  going  to  do  to  correct  these  problems.  And  then  all  this — 
this  report  also  goes  to  a  quality  assurance  committee  which  we 
have. 

We  have  a  standing  committee  where  all  of  these  reports  go  to 
their  review  and  their  suggestions  as  to  what  kind  of  punitive  ac- 
tion should  be  taken.  The  investigator  is  notified  about  these;  he 
is — he  or  she  is  supposed  to  provide  the  NSABP  with  a  plan  of  ac- 
tion that  will  be  acceptable,  and  if  it  is  acceptable,  then  the  deci- 
sion is  made  to  give  them  a  chance  to  show  that  they  have  cor- 
rected themselves  and  resume  accrual.  If  it  is  not  acceptable,  ac- 
crual continues  to  be  suspended. 

Mr.  DiNGELL.  Well,  that  is  all  very  good.  Were  you  ever  made 
aware  of  the  fact  that  there  were  problems  with  informed  consent? 
Were  you  ever  made  aware  of  the  fact  that  there  were  problems 
with  sites  not  maintaining  drug  logs?  Were  you  ever  made  aware 
of  the  fact  that  a  number  of  locations  had  problems  with  missing 
data? 

Mr.  Fisher.  As  I  said,  I  have  seen  these  reports  sent  to  me  by 
Dr.  Wickerham.  At  this  moment  I  don't  know  what  was  in  the  re- 
ports, how  many  of  them  were  related  to  informed  consent,  how 
many  of  them  were  related  to  drug  log  problems.  I  am  unable  to 
answer  that,  sir. 

Mr.  DiNGELL.  Well,  you  are  able  to  tell  us  what  was  done  about 
these  matters.  What  was  done  about  the  informed  consent  ques- 
tion? What  was  done  about  the  questions  on  the  number  of  sites 
that  were  not  maintaining  drug  logs?  What  was  done  about  the 
sites  where  there  were  problems  with  missing  data?  What  action 
did  you  take? 

Mr.  Fisher.  Well,  we  sent  the  reports  back.  One  of  the  purposes 
of  an  audit  program,  aside  from  what  I  mentioned,  is  also  that  it 
is  supposed  to  be  and  is  a  program,  an  interactive  program  where 
investigators  are  informed  about  their  deficiencies  and  are  edu- 
cated against  doing — repeating  this. 


177 

Mr.  DiNGELL.  What  did  you  do  about  these  matters  to  correct  the 
situation,  either  in  general  or  in  any  particular  case?  Did  you  do 
anything?  Can  you  tell  us  any  one  thing  you  did  on  any  one  of 
these  audits  which  came  to  your  attention?  Did  you  do  anything 
about  any  of  the  audits  which  came  to  your  attention  with  regard 
to  either  the  questions  of  informed  consent,  questions  of  inadequate 
drug  logs,  or  failure  to  maintain  drug  logs,  and  also  locations  that 
had  problems  with  missing  data?  Can  you  tell  us  anything  you  did 
about  any  one  of  the  audits  on  any  one  of  these  points? 

Mr.  Fisher.  I  certainly — my  main  issue  here  would  have  been  to 
order  the  personnel  who  were  responsible  for  this  program  to  carry 
out  what  they  were  supposed  to  do. 

Mr.  DiNGELL.  Well,  what  were  you  doing  while  these  people  were 
supposed  to  do  these  things? 

Mr.  Fisher.  I  think  what  we  were  doing,  sir,  is  that  the  NSABP 
did  have  continuing,  ongoing  workshops,  meetings  for  data  man- 
agers, for  all  kinds  of  people  to  educate  them  into — to  try  to  get 
them  to  prevent  this  kind  of  practice.  This  was  what  was  being 
done. 

Mr.  DiNGELL.  What  was  your  job  at  NSABP? 

Mr.  Fisher.  My  main  role  in  the  NSABP,  and  I  take — but  let  me 
emphasize  that  I  take  full  share  of  responsibility — full  responsibil- 
ity for  the  administrative  errors  which  took  place  under  my  term, 
but  I  was,  as  I  mentioned  in  my  introductory  statement,  my  main 
interest  was  to  be — to  try  to  do  the  best  science  that  would  be  pos- 
sible, which  would  affect  the  most  women  in  the  world  with  breast 
cancer.  I  was  on  top  of  the  development  of  the  scientific  program, 
the  implementation  of  the  scientific  program,  the  pooling  together 
of  the  information  and  the  publication  of  the  science,  and  these 
were  the  chief  efforts  that  I  conducted. 

Mr.  DiNGELL.  Well,  let's  look.  What  was  your  job  at  the  NSABP? 

Mr.  Fisher.  As  I  say 

Mr.  DiNGELL.  You  were  the  head  of  the  whole  operation,  were 
you  not? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  And  you  got  these  audit  reports? 

Mr.  Fisher.  I  take  responsibility  for  the  operation;  I  wasn't  the 
head  of  all  of  the  pieces  that  were  under  me.  The  biostatistical  cen- 
ter, the  data  center  which  is  a  major  part  of  the  NSABP;  it  actually 
receives  more  of  the  funding  than  does  the  operations  center. 

Mr.  DiNGELL.  Who  was  responsible  for  management  and  admin- 
istration? 

Mr.  Fisher.  The  management  and  administration  was  delegated 
in  certain  areas.  The  fiscal  administration 

Mr.  DiNGELL.  To  who? 

Mr.  Fisher  [continuing].  — Was  given  to  a  fiscal  officer  who  had 
been  with  me  for  20  years  who  had  a  staff  of  people  that  conduct 
all  of  the  fiscal  affairs  in  concert  with  the  University  of  Pittsburgh 
fiscal  office.  All  of  that  was  integrated. 

Mr.  DiNGELL.  What  did  this  individual  do  with  the  audits?  Did 
he  do  anything  with  them? 

Mr.  Fisher.  At  one  time  Ms.  Dash,  who  was  the — was  the  fiscal 
officer,  her  job  was  to — all  of  the  audit  reports  came  to  her  before 


178 

they  were  finally  sent  out,  and  it  was  her  job  to  see  that  they  did 
get  distributed. 

Mr.  DiNGELL.  Did  this  person  report  to  you? 

Mr,  Fisher.  She  always  reported  to  me  as 

Mr.  DiNGELL.  She  was  responsible  to  you,  was  she  not? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  And  you  were  responsible  for  her;  is  that  right? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  Now,  the  chief  auditor,  Marjorie  McLaughlin,  told 
the  subcommittee  staff  there  were  a  number  of  chronically  prob- 
lematic sites,  such  as  Tulane  and  LSU.  Were  there  any  special  ef- 
forts taken  to  try  to  deal  with  the  sites  that  seemed  to  come  up 
year  after  year  to  exhibit  an  inability  to  follow  the  protocols  of  the 
study? 

Mr.  Fisher.  Yes,  sir.  In  talking  with  the  principal  investigator  on 
many  occasions  by  myself  and  by  our  staff,  there  was  a  Catch-22 
in  that  situation. 

Mr.  DiNGELL.  What  was  the  Catch-22,  Doctor? 

Mr.  Fisher.  Well,  the  Catch-22  was  simply  this,  and  this  has 
been  a  part  that  we  had  experienced  over  many  years.  The  institu- 
tions that  put  on  the  larger  numbers  of  patients  who  did  put  on 
large  numbers  of  patients,  if  they  had  problems  and  if  those  insti- 
tutions were  to  be  eliminated  from  the  NSABP,  the  backlog,  the 
large  numbers  of  patients  that  needed  to  be  followed  up  still  re- 
mained there  to  be  followed  up.  And  so  we  did  keep  those  people, 
when  we  suspended  them,  we  kept  them  on  for  at  least  follow  up, 
until 

Mr.  DiNGELL.  Well,  I  have  no  quarrel  with  follow  up;  I  will  con- 
cede that  this  is  very  important.  But  that  would  be  a  part  of  the 
research  protocols  in  any  event,  that  they  had  to  follow  up;  would 
it  not?  If  only  to  assure  the  health  and  the  safety  and  the  well- 
being  of  the  patient. 

Mr.  Fisher.  Absolutely. 

Mr.  DiNGELL.  All  right.  So  they  had  that  responsibility,  whether 
they  remained  in  the  test  program  or  not.  But  was  there  ever  any 
disciplinary  action  taken  against  Tulane  or  LSU  or  any  of  the  oth- 
ers which  were  either  chronic  problem  areas  or  which  failed  to  deal 
properly  with  the  problem  of  informed  consent,  or  which  failed  to 
keep  proper  drug  logs,  or  which  had  serious  problems  with  missing 
data? 

Now,  we  have  established  that  you  had  all  of  these  difficulties, 
and  I  am  trying  to  find  out  what  one  thing  that  you  did  with  re- 
gard to  any  of  the  sites  which  were  deficient,  some  of  which,  as  we 
have  indicated,  were  chronically  problem  sites  and  others  of  which 
had  significant  failures. 

Now,  what  one  thing  did  you  do  or  what  one  thing  did  anybody 
else  do  about  these  sites  which  were  problems? 

Mr.  Fisher.  We  suspended  their  accrual  and  gave  them 

Mr.  DiNGELL.  When  did  you  do  that?  How  many  of  them  did  you 
do  that  to? 

Mr.  Fisher.  How  many  of  them  did  we  do  that  to?  In  the  last 
cycle  4  in  which  we  did  154  audits — 129  audits;  I  think  there  were 
6  that  were  suspended. 


179 

Mr.  DiNGELL.  But  they  were  suspended,  and  for  how  long  were 
they  suspended? 

Mr.  Fisher.  As  I  recall,  for  varying  periods  of  time,  depending 
upon  what  the  problem  was,  how  rapidly  they  could  get  it  cor- 
rected. I  can't — I  don't 

Mr.  DiNGELL.  Who  were  the  six  that  were  suspended? 

Mr.  Fisher.  I  don't  have  that  at  my  fingertips. 

Mr.  DiNGELL.  Were  Tulane  or  LSU  suspended? 

Mr.  Fisher.  Not  in  the  last  cycle,  no.  Earlier,  but  not  in  the  last 
cycle. 

Mr.  DiNGELL.  But  your  auditors  tell  us  they  were  chronic  prob- 
lems. Now,  what  did  suspension  mean?  Did  suspension  mean  that 
they  were  removed  from  the  test,  they  were  removed  from  the  test 
until  they  had  corrected  the  problems? 

Mr.  Fisher.  They  were  unable  to  put  any  more  patients  on  to  the 
studies  until  those  problems  were  corrected.  We  hoped  to  keep 
them  there,  to  keep  the  patients  followed  that  were  there,  and  that 
was  it. 

Mr.  DiNGELL.  But  they  continued  to  participate  with  the  patients 
that  they  had  on  in  the  program;  is  that  right? 

Mr.  Fisher.  They  continued,  they  continued,  but  didn't  have  any 
activity,  other  than  what  you  say. 

Mr.  DiNGELL.  OK.  So  they  are  continuing  to  submit  data. 

Now,  have  you  suspended,  let's  say,  institution  X  for  bad  data 
and  missing  data?  You  kept  them  on  to  continue  with  their  efforts 
and  to  continue  supplying  missing  data? 

Mr.  Fisher.  No.  We  certainly  did  not.  We  tried  to  provide  them 
with 

Mr.  DiNGELL.  Well,  you  told  us  you  had  kept  them  on  and  you 
kept  them  on.  You  didn't  allow  them  to  enroll  new  patients,  but 
you  kept  them  on.  So  you  kept  them  on  and  they  continued  the 
same  practices.  They  continued  the  same  practices  with  regard  to 
failure  to  achieve  proper  informed  consent,  failure  to  maintain 
proper  drug  logs,  and  failure  to  provide  adequate  data. 

What  I  am  trying  to  find  out  is  what  disciplines  did  you  have, 
what  did  you  do,  how  did  you — how  were  you  able  to  tell  us  when 
your  own  chief  auditor  tells  us  that  there  were  a  number  of  chron- 
ically problematic  sites,  and  I  am  asking  you  what  did  you  do  about 
any  one  of  these  to  see  to  it  that  they  corrected  their  bad  practices? 
What  did  you  do  about  to  see  that  they  corrected  their  bad  prac- 
tices? You  suspended  them,  but  they  continued  apparently  accord- 
ing to  your  chief  investigator,  providing  bad  information,  and  en- 
gaging in  other  practices  which,  quite  frankly,  raise  questions 
about  the  value  and  the  integrity  of  the  scientific  process  involved 
in  this  particular  study. 

Mr.  Fisher.  Sir,  I  cannot  answer  these  questions  unless  I  know 
the  specific  cases  and  so  on.  I  am  sorry.  We  continue  to  try  to  edu- 
cate these  people. 

Mr.  DiNGELL.  It  is  my  impression  that  you  were  the  man  that 
ran  this  whole  thing. 

Mr.  Fisher.  The — in  terms  of  our  involvement  with  these  prin- 
cipal investigators,  we  did  talk  to  them;  we  did  try  to  educate  their 
data  managers;  we  did  try  to  have  affirmative  kinds  of  things  in 
that  nature. 


180 

Mr.  DiNGELL.  But  your  auditors  continued  to  find  chronic  prob- 
lems. 

Mr.  Fisher.  I  don't  know. 

Mr.  DiNGELL.  Didn't  they  tell  you,  we  have  a  problem  here,  and 
didn't  you  in  looking  at  the  audit  say,  by  golly,  we  saw  them  last 
week  or  last  month  or  last  year  and  we  saw  them  the  month  before 
that  and  the  year  before  that  and  the  month  before  that  and  the 
year  before  that?  Were  you  paying  any  heed  at  all  to  these  matters, 
Doctor,  or  were  you  delegating  it  to  somebody  who  was  not  report- 
ing to  you,  or  were  they  reporting  to  you  and  you  not  paying  heed 
to  them? 

Apparently  the  auditors  sent  you  reports  with  which  you  do  little 
or  nothing,  and  apparently  the  chief  auditor  tells  us  about  a  num- 
ber of  chronic  problems  sites.  And  apparently  the  people  whom  you 
delegated  to  deal  with  the  administrative  end  of  the  business  didn't 
deal  with  the  administrative  end  of  the  business  in  terms  of  bring- 
ing it  to  your  attention,  or  if  they  did,  you  didn't  pay  heed  to  it  be- 
cause the  situation  went  on  over  the  entirety  of  the  years.  What 
can  you  tell  us  about  this? 

Mr.  Fisher.  I  can  tell  you  that  I  accept  responsibility  for  any  in- 
adequacies that  took  place,  and  I  am  very  sorry  for  that,  and 

Mr.  DiNGELL.  Here  is  another  question.  Let's  take  Memorial  Can- 
cer Research  Foundation,  Dr.  David  Plotkin.  They  were  identified 
by  NSABP  auditors  in  a  report  in  1990,  and  a  transmittal  letter 
with  findings  was  to  be  shipped  to  Dr.  Plotkin  and  to  NCI.  The 
signed  letter  and  the  envelope  sat  in  NSABP  files  until  recently 
and  the  audit  report  never  left  the  NSABP.  How  did  this  happen? 

Mr.  Fisher.  I  did  not  know  about  this  until  others  knew  about 
it. 

Mr.  DiNGELL.  Well,  let's  assume  that  it  is  true,  and  I  believe  that 
it  is.  You  never  notified  the  people  about  their  failures.  The  audit 
report  never  left  the  NSABP. 

Mr.  Fisher.  I  don't  know,  sir.  It  may  not  have  or  it  may  have. 

Mr.  DiNGELL.  I  am  going  to — I  have  to  go  to  the  Floor;  I  am 
going  to  ask  Mr.  Brown  to  continue  presiding.  I  will  be  back  just 
as  quickly  as  I  can. 

Mr.  Brown,  would  you  take  the  chair  please,  sir. 

Mr.  Brown  [presiding].  I  thank  the  chairman.  The  gentleman 
from  Colorado,  Mr.  Schaefer. 

Mr.  Schaefer.  Thank  you,  Mr.  Chairman. 

Dr.  Fisher,  after  the  media  broke  the  story  on  the  data  falsifica- 
tion by  Dr.  Poisson,  you  purportedly  reanalyzed  the  data  and 
briefed  ORI.  Dr.  Bivens  told  us  in  April  that  your  presentation  was 
oral  and  was  not  written;  is  that  correct? 

Mr.  Fisher.  Presentation  to  the  ORI,  the  NCI,  NIH  people  was 
presented  orally  in  19 — March  1992  at  their  request.  There  had 
been  many  reanalyses  done  by  the  five  statistical  centers  of  the 
NSABP,  Dr.  Redmond  and  her  associates.  She  did  one  almost  im- 
mediately following  the  finding  of  the  first — the  proof  of  falsifica- 
tions. She  did  another  one  which  was  presented  at  this  meeting 
that  you  are  referring  to.  There  were  others  that  were  done  subse- 
quently and  at  one  point  material  of  a  reanalysis  was  submitted  to 
the  NCI.  So  that  there  were  repeated  reanalyses. 


181 

And  at  the  time  of  the  one  at  the — one  that  was  presented  to  the 
ORI,  it  is  my  recollection  that  there  was  total  acceptance  of  this 
audit — of  this  reanalysis,  and  there  were  no  comments  either  spo- 
ken or  written  to  us  regarding  any  concerns  about  the  reanalysis. 

Mr.  SCHAEFER.  Well,  so  it  was  oral.  And  is  this  the  common  prac- 
tice not  to  do  this  in  writing? 

Mr.  Fisher.  It  is  what  we  were  asked  to  do,  sir. 

Mr.  ScHAEFER.  Asked  to  do  by 

Mr.  Fisher.  Asked  to  do  by  the  ORI. 

Mr.  Schaefer.  By  ORI? 

Mr.  Fisher.  Yes,  sir. 

Mr.  Schaefer.  All  right.  Now,  was  this  a  complete  reanalysis? 

Mr.  Fisher.  Yes,  sir.  Complete  reanalysis  of  all  protocols  which 
Dr.  Poisson  had  submitted  patients  to. 

Mr.  Schaefer.  Was  this  a  running  update,  though,  over  a  period 
of  time  where  you  kind  of  looked  at  new  things  all  the  time? 

Mr.  Fisher.  No,  sir.  No.  It  was  a  complete  update  at  one  time, 
one  point  in  time. 

Mr.  Schaefer.  All  right.  At  the  hearing  we  had  in  April,  we 
were  told  that  it  was  not  a  complete  reanalysis. 

Mr.  Fisher.  To  the  best  of  my  knowledge,  sir,  and  the  best  of  my 
remembrance,  it  was 

Mr.  Schaefer.  And  it  has  been  done  since  then? 

Mr.  Fisher.  It  has  been  done  since  then  many  times,  yes. 

Mr.  Schaefer.  Yes,  but  since  April? 

Mr.  Fisher.  It  has  been  done  since  April,  yes.  I  am  terribly  sorry 
that  Dr.  Redmond  isn't  here,  because  Dr.  Redmond,  who  is  the 
statistician  who  is  in  charge  of  all  of  this,  would  better  address 
these  issues  than  I  can. 

Mr.  Schaefer.  Well,  again,  as  the  chairman  spoke,  you  were  in 
charge  of  this  whole  thing? 

Mr.  Fisher.  Absolutely. 

Mr.  Schaefer.  So  therefore,  you  know,  sooner  or  later  the  buck 
stops  somewhere. 

Mr.  Fisher.  Right,  sir. 

Mr.  Schaefer.  This  Dr.  Poisson,  what  is  he  doing  these  days? 

Mr.  Fisher.  I  haven't  the  vaguest  idea. 

Mr.  Schaefer.  After  you  were  made  aware  of  the  fraud  that  had 
been  perpetrate  by  Dr.  Poisson,  you  stated  that  you  immediately 
notified  NCI.  Tell  me,  did  you  ever  notify  the  editors  of  the  New 
England  Journal  of  Medicine  or  any  other  publications  about  this 
so  that  some  of  your  colleagues  would  know  what  was  going  on? 

Mr.  Fisher.  No,  sir,  because  at  that  point  in  time  we  were  em- 
bargoed by  the  ORI,  for  during  their  entire  investigation,  we  were 
only  permitted  to  present — to  tell  people  about  this  under  a  need 
to  know,  and  there  was  no — so  to  answer  your  question,  no,  we  did 
not. 

Mr.  Schaefer.  Now,  you  say  you  were  embargoed,  but  you  still 
provided  this  to  NCI,  this  information? 

Mr.  Fisher.  I  am  sorry. 

Mr.  Schaefer.  You  say  you  were  embargoed,  but  you  still — you 
provided  the  information  on  the  fraudulent  findings  to  the  NCI? 

Mr.  Fisher.  Well,  that  was  certainly  a  need  to  know. 

Mr.  Schaefer.  But  that  was  as  far  as  it  went,  then? 


182 

Mr.  Fisher.  Yes,  sir.  We  did  get  one — we  requested  from  the  ORI 
that  we  be  permitted  to  report  this  to  our  NSABP  executive  com- 
mittee so  that  they  knew  what  was — that  this  was  an  affair  that 
was  going  on. 

Mr.  SCHAEFER.  What  was  the  answer? 

Mr.  Fisher.  And  we  did  give  it  to  them,  to  the  executive  commit- 
tee. In  February  of  1992,  we  presented  the  fact  that  this  was  going 
on  and  we  also  presented  them  with  one — with  the  reanalysis  to  in- 
dicate to  them  that  taking  all  of  the  data  out  in  all  of  these 
reanalyses  failed  to  influence  the  outcome — either  the  outcomes  or 
conclusions  of  any  of  our  studies  that  had  been  previously  reported. 

Mr.  Schaefer.  So  therefore,  now  the  embargo  is  lifted? 

Mr.  Fisher.  Yes,  sir. 

Mr.  Schaefer.  OK.  Then  did  you  inform  the  New  England  Jour- 
nal of  Medicine  or  any  other  publication  of  this,  and  if  not,  why 
not? 

Mr.  Fisher.  I  guess  the  most  direct  answer  to  your  question  is 
that  why  we  did  not  immediately  or  otherwise  inform  them  is  be- 
cause we  really  didn't  know  that  this  was  necessary  to  do. 

Mr.  Schaefer.  Even  though  you  knew  there  was  fraud  there? 

Mr.  Fisher.  The  point  is  that  doing  all  of  these  reanalyses  did 
not  in  any  way  alter  the  outcomes  or  conclusions  of  our  studies. 
There  was  no  alteration  whatsoever,  and  so  therefore,  that  is 

Mr.  Schaefer.  All  right.  Let  me  get  this  straight,  then.  So,  no, 
you  did  not  inform  any  medical  journals  of  this  falsified  data? 

Mr.  Fisher.  I  am  sorry. 

Mr.  Schaefer.  You  did  not  inform  any  medical  journals  of  this 
data  after  the  embargo  was  lifted? 

Mr.  Fisher.  At  that  time,  right. 

Mr.  Schaefer.  You  did  not. 

Mr.  Fisher.  Right. 

Mr.  Schaefer.  I  have  a  little  bit  of  trouble  figuring  out  why  you 
wouldn't  when  we  have  all  of  these  women  throughout  the  country 
who  are  looking  at  these  procedures  or  possible  procedures  trying 
to  figure  out  which  way  they  should  go  and  we  have  doctors  all 
over  the  place  that  would,  I  would  think,  dearly  love  to  have  this 
information. 

Mr.  Fisher.  Well,  as  I  have  said,  there  was  no  evidence  in  any 
way  that  these  data  had  been  changed,  that  the  outcomes  had  been 
changed,  and  therefore,  we  did  not  really  perceive  this  as  a  major 
problem,  public  health  problem  or  otherwise,  and  again,  as  I  said 
in  my  remarks,  had  I  been  circumspect  enough  to  think  that  in 
March  of  1994  this  would  have  become  the  problem  that  it  has,  cer- 
tainly we  would  have  been  more  interested  in  doing  so. 

But  let  me  also  say  that  we  did  have  a  plan  of  action  as  to  what 
we  were  going  to  do,  and  that  plan  of  action  was  to  present  a  full 
report  in  a  peer  review  journal  with  a  technical  report  because 
there  is  so  much  data  that,  so  much  information  that  one  single  re- 
port— one  single  paper  could  not  hold  it. 

The  strategy  of  the  biostatistical  center,  biostatisticians  was  to 
do  that,  have  a  full  technical  report  available  to  everybody  and 
have  a  paper  which  would  indicate  what  the  findings  were. 

Mr.  Schaefer.  If  they  asked  for  it. 


183 

Mr.  Fisher.  To  publish  the  paper,  pubUsh  the  paper  in  a  journal, 
but  a  technical  report  on  file. 

Mr.  SCHAEFER.  Now,  let  me  also  get  this  straight.  You  are  saying 
that  the  fraud  did  not  change  results  of  the  study;  is  this  correct? 

Mr.  Fisher.  Yes,  sir. 

Mr.  Schaefer.  I  have  a  tough  time  figuring  this  one  out.  I  am 
obviously  not  a  medical  doctor,  but  it  seems  to  me  if  there  was 
fraud  and  there  was  falsification  of  information,  how  could  it  not — 
how  could  it  not? 

Mr.  Fisher.  Well,  I  think  you  raise  a  very  important  question 
and  what  you  are  asking  is  a  very,  very  important  one.  And  it  gets 
into  the  problem  of  what  do  you  do  with  the  kind  of  data  that  were 
obtained,  oh,  falsified  data  or  even  ineligibility  patients  and  all  of 
that  sort  of  thing. 

Now,  there  is  a — the  biostatistical  community,  the 
biostatisticians  have  a — their  feeling  about  this,  their  belief,  their — 
most  of  the  major  statisticians,  Professor  Pita  from  Oxford,  who  is 
one  of  the  leading  statisticians  in  the  world,  et  cetera,  et  cetera, 
feel  that — ^you  have  several  choices  when  you  are  faced  with  infor- 
mation like  this.  You  can  either  take  all  of  the  data  out  in  doing 
your  reanalysis,  just  throw  it  all  away,  or  you  can  only  take  out 
that  which  was  the  flawed  data.  In  other  words,  in  the  lumpectomy 
study  of  these  thousands  of  patients,  there  were  only  six  where  it 
was  demonstrated  that  there  was  truly  fraudulent  data.  And  you 
can  get  rid  of  those. 

So  you  can  take  them  all  out,  take  out  just  those  that  are  fraudu- 
lent, or  you  can  leave  them  all  in.  And  this  is  known  as  the  intent- 
to-treat  principle.  And  that  is — so  that  is  a  consideration. 

And  the  statisticians  in  the  NSABP  reached  their  own  conclusion 
that  they  felt,  and  that  was  one  of  the  things  after  the  April — dur- 
ing the  entire  process,  their  intent  was  to  use  the  intent-to-treat 
principle. 

Mr.  Schaefer.  All  right.  If  we  leave  this  information  in,  the 
fraudulent  information  in,  do  you  not  feel  that  the  American  public 
has  a  right  to  know? 

Mr.  Fisher.  We  didn't  leave  it  in,  we  took  it  out.  We  took  it  all 
out. 

Mr.  Schaefer.  Well,  regardless,  it  just  seems  to  me  that  women 
out  there  should  know  whether  a  study,  conducted  with  American 
taxpayers  money  included  fraudulent  information.  This  was  not  di- 
vulged. That  is  what  I  don't  understand  and  what  the  chairman 
doesn't  understand  and  this  whole  committee  doesn't  understand. 
Why  wasn't  this  divulged? 

Mr.  Fisher.  We  had  a  plan  for  divulging  it  in  a  rational,  regular 
basis. 

Mr.  Schaefer.  Yes.  But  that  was  after  a  number  of  women  in 
this  country  had  this  surgery  already. 

Mr.  Fisher.  Nothing  from  our  findings  indicated  that  they  had 
any  improper  therapy. 

Mr.  Schaefer.  I  guess — and  I  know  my  time  is  up  and  I  will  be 
back  for  some  more  questions,  but  it  just  seems  to  me  for  them  to 
make  an  important  decision  like  this  on  whether  they  go  with 
lumpectomy  or  mastectomy,  they  have  to  have  every  possible  shred 
of  information  that  is  out  there.   If  there  is  fraudulent  data  in 


184 

there,  they  should  be  there  for  them  to  make  this  decision.  Maybe 
only  six  of  them  turned  up  problems  or  whatever  it  is — this  has  to 
weigh  heavily  on  whatever  the  final  analysis  is  by  this  individual 
woman.  That  is  what  really  concerns  me. 

I  yield  to  the  chairman  now  and  I  will  come  back  again. 

Mr.  Brown.  Thank  you,  Mr.  Schaefer. 

Mr.  Fisher.  I  would  just  like  to,  Mr.  Schaefer,  say  and  empha- 
size that  these  falsified  data  did  not  alter  the  data,  and  I  would 
emphasize  what  I  said  in  my  preliminary  remarks  that  women  in 
this  country  do  not  need  to  be  worried  about  having  a  lumpectomy, 
because  not  only  have  we,  as  I  said,  our  data,  but  those  from 
around  the  world  and  by  other  people,  also  indicate  that 
lumpectomy  is  an  appropriate  therapy  for  breast  cancer. 

Mr.  Brown.  Mr.  Schaefer? 

Mr.  Schaefer.  I  am  sorry,  Mr.  Chairman,  I  have  to  come  back 
on  this  one.  Well,  for  you  and  I,  we  will  never  have  to  worry  about 
whether  we  decide  to  have  a  mastectomy  or  a  lumpectomy,  but 

Mr.  Fisher.  Well,  sir,  I  have  two  daughters  and  I  have  a  wife 
and  I  have  females  around  me,  and  I  think  all  of  us  have  to  worry, 
male  or  female. 

Mr.  Brown.  Continue. 

Mr.  Schaefer.  Yes.  We  all  have  a  right  to  know. 

Mr.  Fisher,  you  said  if  your  reanalysis  had  produced  evidence 
that  the  conclusions  of  the  study  were  affected  by  the  data  alter- 
ations, you  would  have  reported  those  findings  immediately.  This 
seems  to  indicate  that  it  is  acceptable  to  not  report  findings  of 
fraud  unless  the  fraud  is  determined  to  change  the  findings  of  the 
study.  Do  you  believe  that? 

Mr.  Fisher.  No,  I  don't  believe  that  necessarily. 

Mr.  Schaefer.  Is  it  yes  or  no? 

Mr.  Fisher.  During  the — when  the  material  was — we  were  really 
under  an  embargo  until  the  ORI  report 

Mr.  Schaefer.  I  understand.  I  am  asking  you  personally. 

Mr.  Fisher.  Yes. 

Mr.  Schaefer.  Is  it  acceptable  to  not  report  the  findings,  yes  or 
no? 

Mr.  Fisher.  No,  it  is  not  acceptable  to  not  report  the  findings. 

Mr.  Schaefer.  OK.  Well  then,  the  actions  of  somebody  are  cer- 
tainly inexcusable  in  this  situation. 

Mr.  Brown.  Dr.  Fisher,  I  am  still  unclear.  My  understanding  is 
you — you  said  you  removed  the  bad  data,  but  my  understanding  is 
you  published  papers  after  that,  you  submitted  papers  after  that 
with  the  bad  data  in  them.  Is  that  not  correct? 

Mr.  Fisher.  Those  data  were  included  when  the  biostatistical 
group  and  so  on  decided  that  there  was  a  need  to  invoke  the  intent- 
to-treat  principle  which  meant  leaving  in  all  information. 

Now,  there  is  another  reason,  too,  for  leaving  in  all  of  the  St.  Luc 
patients,  which  I  failed  to  mention,  and  that  is  particularly  would 
it — by  taking  out  all  of  that  data,  let  me  repeat  that,  of  the — there 
were  99  out  of  1,500  patients  in  the  St.  Luc  database  which  had 
falsified  data.  All  of  these  other  women  were  all  of  the  women,  and 
these  falsified  data  related  to  patient  entry  information. 

But  all  the  women  were  real  patients,  real  women  who  all  had 
breast  cancer.  They  were  all  randomized.  They  were  all  followed 


185 

up.  There  was  no  alteration  in  the  treatment  that  was  given,  and 
one  of  the  things  that  by  taking  out  all  patients  prevents  you  from 
doing  is  to  determine  the  toxicities  and  so  on  of  continued  follow 
up.  And  that  is  one  of  the  reasons  that  the  biostatistical  community 
feels  very  strongly  about  for  leaving  patients  in. 

Mr.  Brown.  Didn't  you  just  tell  Mr.  Schaefer  that  the  bad  data 
was  taken  out? 

Mr.  Fisher.  It  was.  In  all  of  the 

Mr.  Brown.  Now  you  are  saying  some  of  it  was  included,  you 
said  in  response  to  my  question. 

Mr.  Fisher.  In  January  of  1993,  we  received  a  letter  from  the 
NCI  stating  that  all  of  the  data  should  be  removed  from  what  we 
interpreted  to  be  any  papers  publishing  new  data,  data  that  had 
never  been  published  before.  Up  until  that  time,  we  had  no  guide- 
lines as  to  not  to  doing  otherwise. 

Mr.  Brown.  But  you  had  no  guidelines  not  to  do  otherwise.  But 
don't  you  know  that  if  you  are  including  this  bad  data  that  you  at 
least  have  some  disclosure  of  it  without 

Mr.  Fisher.  I  wish  I  had  the  biostatisticians  here  to  address  this 
because  it  really  is  an  issue  which  is  very  strong  in  the  statistical 
community  which  indicates  strongly  that  there  are  ethical  consider- 
ations and  statistical  considerations  for  leaving  the  data  in. 

Mr.  Brown.  Well,  maybe  that  is  some  theory  that  statisticians 
understand,  but  don't  you  disclose  that  information  to  the  public 
when,  statistics  aside,  if  it  is  included,  don't  you  disclose  it  and  tell 
people  so  that  the  physicians  know? 

Mr.  Fisher.  We  couldn't  do  it  with  the  embargo  because  it  was 
not  permitted  to  do  that  because  we  would  have  to  admit  where  the 
data  came  from.  By  that  time — that  was  the  reason. 

Mr.  Brown.  You  state  in  your  testimony  that  you  complied  with 
NCI's  request  in  January,  that  no  data  from  St.  Luc  would  be  in- 
cluded in  publications  containing  that  new  data.  The  subcommittee 
had  a  number  of  manuscripts  submitted  after  that  date  where  St. 
Luc  data  was  included.  Can  you  explain  that  discrepancy? 

Mr.  Fisher.  I  will  have  to  review  that,  because  I  don't  know  for 
sure  which  one. 

Mr.  Brown.  You  were — my  understanding  is  you  were  the  author 
of  this,  and  you  cannot  explain  it,  sir? 

Mr.  Fisher.  Which  manuscript  are  you  referring  to? 

Mr.  Brown.  Well,  the  NCI  request  in  January  1993,  JNCI  re- 
garding the  St.  Luc  data.  You  are  not  aware  of  that? 

Mr.  Fisher.  January 

Mr.  Brown.  It  was  NCI's  request  in  January  of  1993 

Mr.  Fisher.  That  was  the  letter  that  came  to  us,  correct,  telling 
us  in  subsequent  publications. 

Mr.  Brown.  And  then  the  paper  was  submitted  a  year  later  with 
the  bad  data. 

Mr.  Fisher.  Which  paper? 

Mr.  Brown.  JNCI. 

Mr.  Fisher.  JNCI.  Oh.  Are  you  referring  to  the  paper  with 
endometrial  cancer? 

Mr.  Brown.  Yes. 

Mr.  Fisher.  That  paper.  Well,  that  was  a  paper  which  was  a 
more  recent  paper  submitted  to  the  JNCI  which  was  the  paper  in- 


186 

dicating  the  information  about  endometrial  cancer.  And  that  infor- 
mation, in  order  to — that  was  providing  information  relative  to  the 
incidence  of  endometrial  cancer  and  the  deaths  from  endometrial 
cancer,  and  that  was  one  of  the  most  important  papers  I  think  we 
have  ever  done  in  that  it  was  able,  for  the  first  time,  to  provide 
some  quantification  of  the  risks  of  getting  endometrial  cancer  in 
breast  cancer  patients  who  received  Tamoxifen,  and  it  would,  in 
order  to  be  absolutely  certain  that  we  weren't  underreporting 
deaths  from  endometrial  cancer,  we  included  the  data  from  St.  Luc 
Hospital  because  to  have  removed  the  data  from  St.  Luc  Hospital 
would  have  underestimated  the  number,  could  have  underesti- 
mated the  number  of  deaths  from  endometrial  cancer,  and  that  was 
what  I  was  referring  to  previously  about  when  you  leave  all  pa- 
tients out,  you  cannot  get  toxicity  or  second  cancers  or  this  kind 
of  thing.  And  that  was  why  that  was  left  and  that  was  a  very  con- 
sidered decision.  It  was  a  decision  that  was  considered — when  I  say 
"considered",  I  mean  that  it  was  given  a  lot  of  thought  and  the 
biostatisticians  decided  that  was  the  appropriate  course  of  action  to 
take. 

Mr.  Brown.  So  you  have  ably  explained  why  you  left  the  bad 
data  in  there.  You  have  had  five  statisticians  and  X  number  of  doc- 
tors that  knew  about  this.  Why  didn't  any  of  you  notify  the  public? 
Why  wasn't  there  any  public  disclosure  other  than  these  five  stat- 
isticians and  these  doctors  that  knew  about  it?  Why  was  there  not 
any  kind  of  disclosure? 

Mr.  Fisher.  There  is  in  the  paper. 

Mr.  Brown.  Not  offered  by  you,  but  ordered  by  NCI,  correct?  Is 
it  true.  Dr.  Fisher,  that  the  paper  was  submitted  without  your  dis- 
closing that  information  from  St.  Luc? 

Mr.  Fisher.  It  was  true  what  you  say,  but  the  final  paper  does 
have  it. 

Mr.  Brown.  In  late  1992,  the  informed  consent  form  for  preven- 
tion trial  participates  was  amended  to  state  affirmatively  that  no 
endometrial  cancer  deaths  had  been  reported;  is  that  correct? 

Mr.  Fisher.  In  late 

Mr.  Brown.  In  late  1992,  that  none  had  been  reported  due  to 
Tamoxifen? 

Mr.  Fisher.  Yes.  To  consent  form. 

Mr.  Brown.  By  that  time,  there  had  been  at  least  one  cancer, 
uterine  cancer  death  known  to  NSABP,  correct? 

Mr.  Fisher.  No,  sir.  No,  that  is  not  so.  At  the  time — at  that  time 
there  were  no  incontrovertible  cases  of  endometrial  cancer  known. 

Mr.  Brown.  You  knew  that  there  was  a  possibility  of  perhaps 
some  link  between  Tamoxifen  and  the  death,  but  it  was  not,  your 
word,  incontrovertible.  So  you  maybe  saw — did  you  see  any  link 
there  at  all  or  you  just  didn't  see  any  absolute  connection? 

Mr.  Fisher.  You  are  talking  about  one  patient  who  had,  and  that 
I  think  the  same  patient  was  discussed  previously  by  previous  dis- 
cussers, and  it  was  a  case  of  a  patient  who  died,  a  patient  died  and 
the  death  certificate  of  that  patient  was  that  this  patient  had 
sepsis  due  to — we  don't  need  to  get  into  the  medical  technicalities, 
although  there  was  a — that  this  patient  actually  died  of  pulmonary 
embolus  and  this  patient  was  coded  and  entered  into  the  system 
of  our  system  as  having  died  of  pulmonary  embolus. 


187 

And  the  information  was  then  obtained  that  this  patient  had  an 
endometrial — had  had  an  endometrial  cancer,  and  this  patient  then 
had  a  breast  cancer.  She  had  an  endometrial  cancer,  she  had  diver- 
ticulitis, she  died  of  pulmonary  embolus,  and  the  question  was,  did 
she  die  from  endometrial  cancer  or  did  she  die  with  endometrial 
cancer? 

We  did  notify  promptly  Zeneca  at  the  time  of  the  regular  annual 
report  of  second  primaries  of  this  endometrial  cancer,  would  have 
been  considered  a  second  primary  tumor,  and  they  were  informed 
that  this  patient  had  died.  We  reported  that  on  1-30-92.  And  then 
there  was  some  question  about  whether  the  patient — ^you  know, 
again  I  emphasize,  and  it  has  got  to  be  emphasized  and  reempha- 
sized,  that  patients  with  breast  cancer  who  subsequently  get 
endometrial  cancer  and  they  die,  do  they  die  from  the  endometrial 
cancer,  do  they  die  from  the  breast  cancer,  or  what?  And  it  was  not 
until  later  that  we  determined  that  there  was  most — the  death  was 
most  likely  due  to  endometrial  cancer,  but  we  were  never  sure.  And 
even  today,  sir,  we  are  not  sure  that  this  first  patient  died  from 
endometrial  cancer,  because  a  recent  review  of  autopsy  slides  by 
pathologists,  several  pathologists  have  suggested  or  raised  the 
issue  that  this  patient  died,  but  she  could  have  very  well  died  from 
breast  cancer  period,  because  in  the  autopsy  review  they  found 
cells  in  the  bone  marrow  which  were  characteristic  of  breast  cancer 
cells. 

And  that — so  that — we  did  call  that  patient  a  death  from 
endometrial  cancer  in  the  report  that  you  referred  to  about  report- 
ing endometrial  cancers,  the  paper,  but  that  is — and  that  is  what 
is  called  an  endometrial  cancer  in  that  paper.  But  we  did  report 
this  to  ICI  as  a  death  from  endometrial  cancer  to  Zeneca  on  12-13- 
93,  when  we  felt  that  the  autopsy  report  became  available  which 
said  endometrial  cancer,  but  there  is  still  a  question  about  that  and 
about  one  other  death  from  endometrial  cancer  where  the  same  sit- 
uation prevailed. 

It  is  a  very,  very  difficult  problem  for  the  pathologists,  for  the 
physician  to  determine  whether  you  have — here  you  have  a  woman 
with  breast  cancer,  she  receives  Tamoxifen  for  her  breast  cancer, 
and  then  subsequently  she  gets  an  endometrial  cancer  and  subse- 
quently to  that  she  dies.  And  to  say  that  she  dies  specifically  from 
endometrial  cancer  under  those  terms  is  very  difficult. 

And  if  one  goes  back  and  looks  at  the  literature  of  patients  who 
have  been  thought  to  have  died  in  several  papers  that  have  been 
reported,  there  is  evidence  that  deaths  in  those  papers  reported 
were  also  related — were  difficult  to  say  were  due  to  endometrial 
cancer  and  not  the  breast  cancer.  So  this  is — it  is  really  truly  a 
medical  dilemma. 

I  am  not — I  reemphasize  firmly  that  this  was  not  withheld  in  any 
way  to  conceal  a  death  from  endometrial  cancer  or  two  deaths  from 
endometrial  cancer;  it  was  purely  a  judgment  related  to  doctors, 
pathologists,  getting  data  and  so  on. 

Mr.  Brown.  Well,  I  understand  as  well  as  a  layperson  can  the 
complexities  of  the  medical  analyses  and  the  difficulty  of  determin- 
ing what  she  might  have  died  of  if  she  had  three  or  four  things, 
any  one  of  which  could  have  caused  her  death. 


188 

How  can  you  affirmatively  say  in  a  consent  form  that  she  did  not 
die  of  endometrial  cancer,  then?  How  can  you  say  that? 

Mr.  Fisher.  These — the  original  consent  form  had — what  you  are 
referring  to  said  there  were  no  deaths  from  endometrial  cancer. 

Mr.  Brown.  Yes. 

Mr.  Fisher.  And  that  was  a — that  is  an  unfortunate  thing  that 
sentence  got  there.  The  original  draft  of  that  consent  form  did  not 
have  that  statement,  the  earlier  draft,  and  then  that  was  there, 
and  that  consent  form,  that  statement  of  no  deaths  from 
endometrial  cancer — let  me  just — may  I  just — do  you  mind  if  I  just 
talk  a  little  bit  about  this,  because  this  is  a  very  difficult  problem 
relative  to  the  consent  forms. 

I  would  only  say  that  we  were  involved  completely  in  the  consent 
form  formulations  with  the  pharmaceutical  manufacturers,  with 
the  NCI,  and  the  NSABP,  and  the  FPA,  and  others  when  these 
various  consent  forms  were  formulated. 

And  as  a  matter  of  fact,  the  statement  of  no  deaths  from 
endometrial  cancer  put  into  that  consent  form,  we  believe,  and 
have  reason  to  believe,  that  statement,  sentence  was  put  in  by  the 
NCI  in  their  review  of  the — in  their — in  the  preparation  of  the  con- 
sent form. 

Mr.  Brown.  Had  you,  Dr.  Fisher,  at  the  time  of  that  death,  when 
speaking  with  NCI  in  understanding  what  had  been  the  consent  in 
the  consent  form 

Mr.  Fisher.  Excuse  me,  sir.  The  fact  that  it  said  no  death  was 
absolutely  right  as  far  as  we  were  concerned  in  that  there  were  no 
specific  deaths  at  that  point  in  time  which  the  NSA 

Mr.  Brown.  So  you  really  didn't  know  that.  If  I  could.  Dr.  Fisher, 
you  really  didn't  know  that  was  the  case,  you  only  knew  that  she 
could  have  died  from  any  one  of  two  or  three  or  four  causes;  you 
didn't  know — you  couldn't  say  which  one  for  sure,  you  couldn't  say 
which  one  not  for  sure. 

Mr.  Fisher.  That  is  exactly  right,  and  that  is  why  we  reported 
to  the  Zeneca  on  1-30-92  that  there  was  a  patient  who  died,  she 
died  and  she  had  that — so  that  patient  was  reported.  We  didn't  put 
in  a  cause  of  death  because  we  weren't  sure  of  what  the  cause  of 
death  was.  But  she  was  a  patient  who  had  died  of — actually,  the 
second  sheet,  these  patients  were  considered  a  second  primary,  peo- 
ple who  got  an  endometrial  cancer  were  second  primary  cancers 
and  they  were  looked  upon  as  like  somebody  who  would  develop  a 
lung  cancer  or  a  colon  cancer,  and  they  weren't  treated  any  dif- 
ferently. 

Mr.  Brown.  How  many  women  might  have  signed  up  for  that 
study  having — having  this  statement  that  no  one  had  died  of  uter- 
ine cancer? 

Mr.  Fisher.  I  can't  answer  that,  sir.  But  let  me  just 

Mr.  Brown.  Can  you  guess?  Is  it  hundreds?  Is  it  thousands? 

Mr.  Fisher.  I  just  don't  know,  because  I  don't  know 

Mr.  Brown.  How  long  did  the  statement  remain  in  there  before 
it  was  corrected  at  the  prodding  of  NCI,  is  my  understanding? 

Mr.  Fisher.  We  reported  the  fact — we  reported  this  in  October — 
end  of  October,  October  31,  to  our  group  meeting  in  Chicago.  The 
reports  of  that  case  and  two  other  cases  were  reported,  and  that 
was  at  that  time,  incidentally,  at  that  meeting,  where  it  was  re- 


189 

ported  Zeneca  personnel  and  NCI  personnel  were  present,  they 
were  present,  and  this  was  reported  at  that  time. 

But  the  consent  form  that  was  in  use,  the  one  you  are  referring 
to,  I  would  only  like  to  call  your  attention  to  the  fact  that  in  that 
consent  form,  it  was  vigorously  described  that  there  were  all  kinds 
of  toxicities  resulting  from  the  use  of  Tamoxifen,  and  it  was  pointed 
out  that  Tamoxifen,  women  on  Tamoxifen  developed  endometrial 
cancer  in  those  three  times  as  great,  and  we  also  showed  that  there 
were  deaths  from  taking  Tamoxifen  due  to  blood  clots  and 
thromboembolism  and  other  complications.  So  women  going  into 
this  study  knew  that  they  were  taking  a  drug  that  did  have  serious 
side  effects. 

Mr.  DiNGELL.  Doctor,  can  you  tell  us  how  long  this  statement 
was  in  effect,  that  no  one  had  died  of  endometrial  cancer? 

Mr.  Fisher.  Subsequent  to  the  meeting  in  Chicago  which,  as  I 
say,  was  October  31,  as  I  recall,  there  was — right  after  that  we  did 
meet  with  the  NCI  in  November,  at  which  time — November  or  De- 
cember, at  which  time  the  material,  a  more  updated  version  was 
presented  to  the  NCI  officials,  and  a  plan,  an  affirmative  plan  was 
immediately  started  to  change  the  consent  form.  And  this  was  im- 
plemented. And  again,  when  we  began  to  do  that,  make  that 
change,  again  I  would  call  your  attention  to  the  fact  that  changing 
a  consent  form  is  not — involves  many  different  agencies.  It  involved 
the  NCI,  it  involved  the  FDA,  OPRR,  it  involved  the  physicians  of 
the  NSABP,  and  so  on.  So  we  had  a  whole  long  list  of  people  or 
agencies  who  wanted  to  take  part  in  the  designing  of  the  new  con- 
sent form  and  they  all  had  their  own  way — intention  of  what  could 
be  done. 

At  the  same  time,  Zeneca  had  called  to  our  attention,  as  did 
other  people,  that  there  were  other  complications  that  needed  to  be 
put  into  that  consent  form,  complications  which  related — things 
that  had  to  be  said  in  that  consent  form  about  pregnancy,  about 
BES,  about  alopecia,  about  second  cancers,  second  intestinal  can- 
cers, and  there  was  a  continuous  interplay  between  all  of  the  peo- 
ple I  mentioned,  together  with  all  of  the  people  who  were  inter- 
ested in  getting  these  various  complications  into  the  consent  form. 
This  led  to  continuous  dialogue  back  and  forth  from  our  people  in 
the  NSABP  with  all  of  the  government  agencies,  and  virtual 
gridlock  existed. 

Mr.  DiNGELL.  All  right.  Now,  Doctor,  the  purpose  of  the  informed 
consent  form  is  to  see  to  it  that  the  person  who  participates  in  the 
test  knows  all  of  the  risks  to  him  or  her  that  are  associated  with 
that  participation;  isn't  that  true? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  That  is  the  whole  reason  for  it.  So  here,  then,  for 
a  period  of  about  a  year,  actually  over  a  year,  this  form  did  not  in- 
dicate the  risk  of  endometrial  cancer  from  the  test;  isn't  that  right? 
Nor  did  it  indicate,  nor  did  it  indicate  during  that  period  of  time 
that  patients  were  at  risk  of  cancer  and  possible  death  from  the 
use  of  Tamoxifen  in  connection  with  this  test  for  a  period  of  better 
than  a  year;  isn't  that  so? 

Mr.  Fisher.  No,  sir.  The  consent  form  did  indicate  that  there  was 
a  threefold  risk  of  getting  endometrial  cancer.  That  was  in  the  con- 
sent form. 


190 

Mr.  DiNGELL.  So  the — it  said  the  risk  of  cancer,  but  it  did  not  say 
the  risk  of  death  of  cancer. 

Mr.  Fisher.  No,  sir. 

Mr.  DiNGELL.  And  it  may  be  that  people  still  equate  cancer  with 
death,  but  it  may  be  they  don't.  But  if  you  just  say  you  get  cancer 
from  this,  it  is  not  quite  as  true  as  saying  people  have  died  of  can- 
cer from  this.  So  for  a  period  of  a  year,  this  form  was  not  brought 
current  with  the  real  state  of  facts,  was  it? 

Mr.  Fisher.  It  was  several  months  I  believe,  I  am  not  sure;  I 
don't  have  the 

Mr.  DiNGELL.  All  right.  Now,  can  you  name  any  of  the  agencies 
that  you  said  had  to  sign  off  on  this  change  who  would  have  ob- 
jected to  assuring  the  fullest  possible  information  to  the  partici- 
pants in  the  test  with  regard  to  the  real  level  of  risk? 

Mr.  Fisher.  I  am  sure  they  would  not  have. 

Mr.  DiNGELL.  So  it  is  not  a  realistic  assumption  that  they  would 
have  resisted  a  change  which  would  have  better  informed  the  peo- 
ple who  were  participating  in  the  test,  is  it? 

Mr.  Fisher.  It  wasn't  a  matter  I  guess  of  resisting;  it  was  a  mat- 
ter at  the  time  of  the  back  and  forth  that  had  to  take  place  to  do 
it. 

Mr.  DiNGELL.  Well,  was  this  question  ever  laid  before  the  agen- 
cies that  you  referred  to?  In  other  words,  that  you  had  the  addi- 
tional— that  you  had  deaths  from  endometrial  cancer,  was  it  laid 
before  these  agencies  or  was  it  not? 

Mr.  Fisher.  Well,  certainly  I  think  that  it  was  laid  before  the 
agencies,  yes. 

Mr.  DiNGELL.  Was  it  laid  before  them  in  connection  with  a  re- 
quest to  change  the  form? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  Well,  so  we  have  come  to  the  conclusion  that  for 
a  little  over  a  year  that  there  was  no  public  statement  with  regard 
to  the  risk  of  death  of  cancer  which  came  out,  nor  was  there  a 
change  in  the  form  during  that  period.  This  is  from  the  period  late 
1992  to  early  1994. 

How  many  women  signed  up  for  participating  in  this  program 
during  that  period  of  time? 

Mr.  Fisher.  I  have  lost  the  thread  of  the  date,  sir,  I  just  have 
lost  it. 

Mr.  DiNGELL.  A  goodly  number,  a  few,  none? 

Mr.  Fisher.  A  goodly  number,  I  would  suspect.  I  am  not  sure 
how  many. 

Mr.  DiNGELL.  When  did  you  first  start  signing  women  up  to  this 
particular  program? 

Mr.  Fisher.  The  program  opened  on  June  1,  1992. 

Mr.  DiNGELL.  So  that  is  approximately  commensurate  with  the 
date  that  you  began  to  have  the  information  with  regard  to  the  risk 
of  death  of  endometrial  cancer? 

Mr.  Fisher.  We  had  no  deaths  from  endometrial  cancer  that 
were  confirmed  at  that  time,  none. 

Mr.  DiNGELL.  How  many  have  signed  up  now? 

Mr.  Fisher.  As  of  March,  when  the  study  was  suspended,  there 
were  approximately  11,000. 


191 

Mr.  DiNGELL.  How  many  of  them  were  warned  with  regard  to  the 
possible  risk  of  death  from  endometrial  cancer  during  this  period? 

Mr.  Fisher.  I  can't  answer  that.  Their  physicians  were  informed, 
and  it  was  the  job  of  the  physicians  to  talk  to  the  people  about 
that. 

Mr.  DiNGELL.  As  a  matter  of  fact,  what  the  people  who  signed 
up  were  told,  according  to  the  public  pronouncements,  was — and 
the  form — that  was  no  one  had  died  of  endometrial  cancer  as  a  re- 
sult of  this  test;  is  that  right? 

Mr.  Fisher.  The  consent  form  said  no  deaths,  but  the  other  thing 
that  consent  form — they  knew  when  they  were  signing  that  consent 
form  that  there  were  a  host  of  other  complications,  including 
endometrial  cancer,  and  there  were  two  deaths  that  had  occurred 
from  thromboembolism,  so  it  wasn't 

Mr.  DiNGELL.  How  many  of  these  11,000  women  who  signed  up 
for  this  program  were  made  aware  of  the  two  deaths? 

Mr.  Fisher.  These  two  deaths  from  thromboembolism?  All  of 
them;  that  was  in  the  consent  form. 

Mr.  DiNGELL.  All  of  them  were  made  aware  of  the  fact  that  there 
were  two  deaths? 

Mr.  Fisher.  Yes,  sir. 

Mr.  DiNGELL.  That  is  somewhat  at  variance  with  your  earlier 
testimony. 

Mr.  Fisher.  Not  deaths  with  endometrial  cancer,  but  deaths  of 
pulmonary  embolism  or  that  sort  of  thing,  the  point  being  that  all 
the  women  who  signed  up  knew  that  tamoxifen  was  not  a  drug 
which  had  no  side  effects  whatsoever. 

Mr.  DiNGELL.  But  we  do  not  quarrel  about  the  fact  that  they 
were  not  told  that  there  were  no  side  effects  to  its  use.  We  are  dis- 
cussing very  specifically  the  deaths  which  occurred  here.  How 
many  were  warned  of  those? 

Mr.  Fisher.  Well,  at  that  time,  when  the  prevention  trials  start- 
ed, we  had  no  evidence  as  far  as  we  can  determine  that  there  was 
specific — that  there  were  patients  who  died  specifically  because  of 
endometrial  cancer. 

Mr.  DiNGELL.  Now,  Doctor,  the  NSABP  has  provided  the  sub- 
committee with  a  number  of  documents  in  the  last  couple  of 
months.  One  of  these  documents  is  a  group  of  slides  dated  August 
1993.  In  these  slides,  there  are  at  least  two  patients  known  to 
NSABP  by  August  1993  to  have  died  from  endometrial  cancer,  yet 
information  on  endometrial  cancer  deaths  was  not  reported  by  you 
to  NSABP  meetings  until  late  October  of  1993,  and  was  not  re- 
ported to  the  drug  manufacturer  until  December. 

Now,  given  the  fact  that  the  prevention  trial  was  actively  recruit- 
ing at  this  time,  why  was  this  information  not  immediately  con- 
veyed in  August,  or  earlier,  so  that  the  informed  consent  form 
could  be  changed? 

Mr.  Fisher.  Sir,  to  the  best  of  my  ability,  I  will  try  to  explain 
that. 

The  date  on  the  slide  was  the  date  at  which  the  Biostatistical 
Center  closes  the  summary  file.  Now,  what  the  summary  file  is,  is 
that  is  the  cutoff  point  that  they  use  for  preparing  their  informa- 
tion. I  myself  did  not — when  the  person  who  made  the  slide,  we  put 
that  on,  and  they  usually  do  because  that  is  the  date  that  is  set. 


192 

but  I  myself  didn't  get  that  information  until  the  slide  was  being 
prepared  for  the  meeting  in  October,  so  that  is  a  discrepancy. 

It  wasn't  that  I  made  that  slide  in  August.  The  slide  was  not 
made  in  August;  the  slide  was  made  in  October. 

Mr.  DiNGELL.  Are  you  telling  us  that  the  NSABP  didn't  tell  you 
about  these  events?  Were  you  aware  or  not  aware? 

Mr.  Fisher.  To  the  best  of  my  knowledge,  I  was  not  aware  of 
them. 

Mr.  DiNGELL.  OK,  you  were  not  aware.  So  then  NSABP  didn't 
tell  you  about  these  two  deaths  from  endometrial  cancer;  shouldn't 
they  have  told  you? 

Mr.  Fisher.  Well,  again,  the  question  about  the  two  deaths  from 
endometrial  cancer,  they  should  have  told  me,  but  there  was  still 
some  question  about  whether  these  were  deaths  from  or  with 
endometrial  cancer. 

Mr.  DiNGELL.  Well,  you  didn't  know  about  it,  so  you  didn't  say, 
OK,  we  ought  to  look  into  this  and  fmd  out.  If  these  things  had 
been  brought  to  your  attention,  you  would  have  said,  we  had  better 
look  into  these  things  and  find  out  whether  these  deaths  are 
caused  by  endometrial  cancer  or  something  else;  isn't  that  right? 
You  certainly  would  have  done  that  if  that  had  been  made  avail- 
able to  you. 

Mr.  Fisher.  I  would  have  hoped  we  would  have  known  sooner  if 
there  were  deaths. 

Mr.  DiNGELL.  But  they  didn't  tell  you,  and  they  didn't  tell  the 
manufacturer. 

Now,  the  manufacturer  has  got  the  possibility  of  lawsuits  against 
him  because  of  the  fact  that  the  people  have  died  of  cancer  from 
taking  this  particular  substance  as  part  of  a  test.  As  a  matter  of 
fact,  NSABP  had  the  possibility  of  lawsuits  against  them.  Univer- 
sity of  Pittsburgh  had  the  possibility  of  lawsuits  against  them. 

Nobody  is  notified  about  the  fact  that  we  have  these  cancer 
deaths  flowing  possibly — and  I  think  we  might  even  say  "prob- 
ably"— from  the  use  of  tamoxifen.  You  were  not  made  aware.  Uni- 
versity of  Pittsburgh  was  not  made  aware,  others  in  NSABP  were 
not  made  aware,  the  manufacturer  is  not  made  aware.  Is  this  good 
administration? 

Mr.  Fisher.  We  reported  this  to  the  group  on  October  31st  to 
the 

Mr.  DiNGELL.  And  the  slide  was  made  in  August? 

Mr.  Fisher.  No,  the  slide  wasn't  made  in  August;  the  slide  was 
made  in  October.  The  slide  was  made  in  October. 

Mr.  DiNGELL.  All  right,  the  data  was  available  in  August.  When 
was  the  slide  made? 

Mr.  Fisher.  The  slide  was  made  for  the  meeting  in  October. 

Mr.  DiNGELL.  But  the  data  was  available  in  August  then? 

Mr.  Fisher.  The  data  was — I  don't  know,  I  can't  answer  that. 

Mr.  DiNGELL.  It  was  significantly  before  the  slide  was  prepared, 
because  the  preparation  there 

Mr.  Fisher.  In  preparing  for  the  slide- 


Mr.  DiNGELL.  Because  the  data  had  been  around  for  a  while. 

Mr.  Fisher.  In  preparing  for  this  meeting,  the  August  30th  data 
set,  that  was  the  cutofi"  that  they  used.  Now,  whether  that  was 
known  or  not  known,  I  don't  know. 


193 

Mr.  DiNGELL.  Well,  here  is  what  the  slide  sheet  on  the  slide  says, 
it  says  endometrial  cancer,  parenthesis,  EC,  in  B-14,  as  of  August 
31,  1993.  This  means  that  prior  to  August  31  there  was  awareness 
in  the  test  program  that  this  was  a  problem. 

Mr.  Fisher.  I  can't  be  sure.  All  I  can  say  is  that  was  when  the 
summary  file  was  closed  in  the  data  center — and  I  apologize  for 
this,  and  I  wish  the  biostatisticians  who  were  responsible  for  this 
kind  of  thing  were  here;  but  they  are  not  here,  and  I  cannot  answer 
the  questions. 

Mr.  DiNGELL.  Let's  go  to  the  next  question  here. 

One  argument  that  has  been  raised  about  audits,  time  limits  and 
the  flow  of  information,  is  that  there  is  a  lack  of  resources  for  that 
function.  Is  that  a  problem? 

Mr.  Fisher.  I  am  sorry? 

Mr.  DiNGELL.  Is  there  a  lack  of  resources  for  dealing  with  ques- 
tions of  audits,  time  limits,  and  information  flow?  In  other  words, 
do  we  not  have  the  resources  that  is  needed  for  that  kind  of  thing? 

Mr.  Fisher.  There  was  a  problem  that  existed.  We — the  peren- 
nial problem  about  funding  in  1991,  when  our  renewal  grant  appli- 
cation was  submitted,  we  had  asked  for  $180,000,  which  then  we 
didn't  get;  we  got  $80,000. 

Mr.  DiNGELL.  The  Chair  is  going  to  recognize  the  gentleman  from 
Colorado,  the  gentleman  from  Colorado. 

Mr.  Schaefer.  Thank  you,  Mr.  Chairman. 

I  want  to  follow  up  on  what  the  chairman  just  touched  on.  This 
member  believes  you  are  a  very  brilliant  doctor,  but  I  am  concerned 
that  there  was  a  problem  of  underadministration.  A  lot  of  the  infor- 
mation that  was  flowing  out  there  through  audits,  et  cetera,  never 
seemed  to  get  to  you.  So,  therefore,  it  seems  to  me  that  we  needed 
to  add  more  administration. 

Now,  did  you  ever  ask  NCI  for  additional  funds  for  administra- 
tion? 

Mr.  Fisher.  Yes,  we  did,  in  the  years  1989,  1990,  1991  and  so 
on.  We  have  in  our  records  letters  were  sent  because  at  that  time 
our  program  was  growing  as  it  continued  to  grow,  and  there  was 
either  level  or  reduced  funding  at  each  year,  and  we  actually  had 
deficits  in  our  budget,  we  requested  support,  and  that  sort  of  thing. 

Relative  to  personnel,  the  addition  of  personnel,  we  realized  the 
need  to  do  that.  We  actually  recruited  for  quality  assurance  people, 
people  to  come  in  that  had  the  kind  of  knowledge  that  could  help 
us.  We  interviewed  four  people  in  the  course  of  a  short  space  of 
time,  or  over  a  period  of  time,  and  none  of  these  people  seemed  to 
be  the  kind  of  people  that  we  would  want  to  have.  It  is  very  dif- 
ficult to  get  somebody  in  without  any  prior  experience. 

There  were  other — there — so  that  those  situations  did  exist. 

And  let  me  also  add  one  thing,  and  that  is  that  Margie 
McLaughlin,  who  was  the  key  auditor  in  the  program  for  20  years, 
resigned,  retired,  and  that  left  the  Biostatistical  Center  with  a  hole 
to  replace.  They  had  started  replacing — training  people  and  so  on. 

Mr.  Schaefer.  All  right.  But  did  you  specifically  ask  NCI  for  ad- 
ministration funds — not  funds  for  the  whole  program,  administra- 
tion funds? 

Mr.  Fisher.  I  believe  so. 


194 

Mr.  SCHAEFER.  You  did  ask  Zeneca  for  funding.  Did  you  ever  ap- 
proach them  on  administration-only  funding? 

Mr.  Fisher.  No,  sir,  never  did.  I  would  have  thought  that  would 
have  been  an  improper  thing  to  do. 

Mr.  SCHAEFER.  Well,  now  I  want  to  get  into  this  reception  thing 
for  just  a  minute.  So  it  is  proper  for  them  to  pay  for  receptions,  but 
not  for  administration  funding.  They  indicated  to  us  that  they  pro- 
vided the  funds  for  the  receptions.  Now,  who  paid  for  the  travel 
and  lodging? 

Mr.  Fisher.  Travel  to  group  meetings  is  included  in  the  budget, 
travel  for  investigators  to  go  to  the  group  meetings.  And  I  would 
emphasize  that  the  Zeneca  people  did — that  this  is  an  entirely  sci- 
entific meeting,  the  business  of  the  group  has  no  other  function, 
and  that  meeting  is  totally  for  that.  And  as  was  explained,  there 
was  a  reception  at  each  of  these  meetings. 

Zeneca,  at  the  beginning  of  this  thing,  sort  of,  you  know,  they 
more  or  less  volunteered  to  do  that  years  ago.  Other  pharma- 
ceutical companies  made  some  contributions,  and  I  personally 
never  would  go  to  Zeneca  and  ask  them,  will  you  give  us  money. 
We  have  people  that  work  in  my  organization  who  have  talked  to 
them  and  so  on. 

Mr.  SCHAEFER.  OK,  getting  back  to  the  question.  I  want  to  un- 
derstand correctly.  Zeneca  and  others  provided  funds  for  the  recep- 
tions, but  the  travel  to  and  from  wherever  it  was,  the  lodging  was 
built  into  your  budget? 

Mr.  Fisher.  Most  of  the  people  who  came  to  the  meetings  paid 
their  own  funds  for  travel,  and  that  came — it  could  have  or  it  could 
not  have  come  from  what  they  had  been  reimbursed  for  the  patient 
payments,  if  they  had  some  money  left  over,  which  I  don't  think 
they  did;  but  that  was  the 

Mr.  SCHAEFER.  So  it  is  fair  to  say,  though,  that  in  many  in- 
stances it  was  taxpayers'  funds  that  provided  this? 

Mr.  Fisher.  Provided  investigators  to  go  to  the  meetings? 

Mr.  SCHAEFER.  Right,  lodging  and  transportation. 

Mr.  Fisher.  Yes,  sir. 

Mr.  SCHAEFER.  OK.  The  fraud  on  the  data  was  discovered  in 
1991;  am  I  correct? 

Mr.  Fisher.  Yes,  sir. 

Mr.  SCHAEFER.  The  embargo  was  lifted  when? 

Mr.  Fisher.  In  April  of  1993. 

Mr.  Schaefer.  ok.  When  you  had  these  semiannual  meetings, 
after  April  of  1993,  were  the  people  who  came  to  these  meetings 
made  aware? 

Mr.  Fisher.  The  plan  was  to  present  this,  as  we  have  said,  in 
a  final  report;  and  actually  that  final  report  coincided  with  this 
current  NSABP  meeting.  That  was  when  it  was  planned  to  be 
done.  At  that  time,  the  biostatisticians  were  to  have  a  complete 
technical  report  which  is  in  the  progress  report  of  this  meeting,  and 
that  was  when  the  whole  thing  was  to  be  presented. 

Mr.  Schaefer.  OK.  When  was  it  presented?  Ever? 

Mr.  Fisher.  At  this  meeting,  right  now. 

Mr.  Schaefer.  So  it  was  actually  done? 

Mr.  Fisher.  I  presented  some  of  this  on  Monday,  Dr.  Redmond 
and  myself. 


195 

Mr.  SCHAEFER.  What  Monday?  When?  What  Monday?  Just  re- 
cently Monday? 

Mr.  Fisher.  Day  before  yesterday. 

Mr.  SCHAEFER.  So  after  the  embargo  was  Ufted  in  April  of  1993, 
you  finally  now  presented  the  information  that  you  had  fraudulent 
data? 

Mr.  FiSHER.  Yes,  sir. 

Mr.  SCHAEFER.  Why  this  long? 

Mr.  Fisher.  I  guess  it  gets  back  to  what  was  talked  about  before, 
and  that  has  to  do  with  when  the  issue  of  the  plan  was  put  in  and 
also  the  other  things  that — where  the  results  didn't  make  any  dif- 
ference, and  then  along  came  a  lot  of  other  things  which  interfered 
with  going  ahead  with  this  paper — at  that  particular  time  you  were 
talking  about,  some  of  the  consent  form  changes,  we  mentioned 
that;  the  problems  with  the  prevention  trial,  there  were  people  who 
were  concerned  about  the  prevention  trial;  the  recruitment  prob- 
lems; and  there  was  always  something  that  was  coming  in  which 
interfered,  which  seemed  to  take  precedence  over  presenting  this. 

Mr.  SCHAEFER.  Well,  maybe  a  lot  of  things  in  your  mind  did  take 
precedence,  but  it  would  seem  to  me  that  this  information  probably 
should  have  been  at  the  top  of  everybody's  list,  particularly  once 
you  tell  me  that  the  embargo  has  been  lifted.  When  it  was  lifted, 
I  don't  see  why  you  immediately  could  not  have  notified  The  New 
England  Journal  of  Medicine  or  other  comparable  publications  and 
gotten  this  word  out  as  fast  as  possible. 

I  might  make  one  final  comment  here.  I  don't  know  what  was 
spent,  in  taxpayers'  dollars,  in  going  to  these  semiannual  meetings 
and  I  am  sure  such  meetings  are  valuable  and  all  that,  but  maybe 
some  of  those  dollars  could  have  been  better  used  for  administra- 
tion costs. 

Mr.  FiSHER.  Well,  sir,  let  me,  if  I  could,  just  for  a  moment,  be- 
cause I  think  this  is  terribly  important  for — at  least  from  my  per- 
spective. 

When  the  NSABP  started  in  1970,  when  we  began— 1971  in 
Pittsburgh — there  were  24  members;  and  today,  as  you  heard, 
there  were  over  500  members,  and  many  thousands  of  physicians, 
over  those  years,  which  have  participated.  And  one  of  the  major 
goals  that  I  had  was  to  make  this  a  community-based  program,  not 
limiting  it  to  physicians. 

In  the  1970's,  there  were  precious  few  physicians  at  cancer  cen- 
ters or  major  centers  who  participated  in  clinical  trials,  so  I  spent 
the  next  10  years  of  my  life,  or  more,  trying  to  convince  physicians 
in  the  community  to  participate  in  the  clinical  trial  program;  and 
I  think  that  worked,  and  it  did  work,  and  community  physicians — 
the  quality  of  medicine  through  that  mechanism  has  been  up- 
graded. And  so  the  scientific  approach  to  practice  of  medicine  has 
been  improved. 

Now,  those  physicians  came  to  these  meetings.  They  didn't  get — 
and  as  was  made  here,  comments  were  made,  whatever  payments 
that  were  given  to  physicians  for — not  to  physicians,  but  for  the 
costs  of  putting  patients  into  clinical  trials  did  not  meet  the  costs 
that  were  needed;  and  I  think  everybody  involved  would  agree  to 
that,  that  the  cost  for  a  patient  in  a  clinical  trial  was  $800  to 
$1,000,  that  sort  of  range.  That  money  was  to  be  used  for  a  lifetime 


196 

of  follow-up  on  those  patients.  It  was  a  one-time  payment,  and 
therefore  it  took  care  of  the  costs  of  the  administrative  activity  at 
each  one  of  these  community  centers  where  they  had  to  have  a 
nurse,  they  had  to  have  a  data  person,  and  it  also  paid  for  follow- 
ing up  patients. 

This  meant  that  private  institutions  all  over  this  countrv  and 
otherwise,  other  circumstances,  were  paying  for  these  people,  for 
these  patients  getting  into  the  clinical  trial. 

Now,  we  did  have  these  meetings  which,  as  I  say,  we  had — first 
of  all,  the  NCI  used  to — they  wanted  a  meeting  twice  a  year,  and 
we  complied  for  a  long  time,  then  it  was  reduced  to  once  a  year. 

As  this  grew  and  it  became  a  1,000  to  1,200  or  1,300  people 
would  come  to  these  meetings,  we  couldn't  find  places  large  enough 
to  accommodate  1,200  or  1,300  people,  and  to  keep  places  where 
the  rates  were  low  enough  to  be  able  to  afford  for  all  of  these  peo- 
ple to  come;  and  we  are  talking  about  the  lowest  possible  room 
rates  and  the  lowest  possible  travel  rates,  et  cetera.  Aiid  the  reason 
for  going  around  to  different  places  in  this  country  was  based  on 
geography — and  you  talked  about  Banff  in  Canada;  yes,  Canada 
has  been  a  major  contributor  to  the  NSABP.  At  one  time  40  per- 
cent of  the  patients  in  the  NSABP  came  from  Canada,  from  Van- 
couver to  Montreal.  Therefore  we  needed  to  have  a  place  to  accom- 
modate a  thousand  or  so  people,  and  it  had  to  be  in  Canada;  and 
we  looked  for  those  places  and  we  found  that  at  this  particular 
place  we  could  get  a  rate  which  was  cheaper  than  in  most  other 
hotels. 

Mr.  SCHAEFER.  OK,  but  you  made  the  decision  then  yourself  on 
where  to  go — Hilton  Head,  S.C.,  or  to  San  Francisco? 

Mr.  Fisher.  I  think  that  was  done,  we  had  a  meeting,  our  own 
group  had  a  person  who  would,  you  know,  find  out  where  the 
places  are,  the  rates  they  could  get,  all  of  this  kind  of  thing,  and 
that  was  how  it  was  made. 

Mr.  SCHAEFER.  I  would  just  suggest  to  the  gentleman — I  don't 
know,  maybe  I  am  really  off  base,  but  Hilton  Head,  S.C.,  I  don't 
know  if  that  is  the  cheapest  place  to  go  around  or  DisneyWorld  or 
the  Fairmont  Hotel  in  San  Francisco,  unless  you  really  pulled  some 
strings. 

Mr.  Fisher.  Well,  I  would  have  to — I  understand,  but  I  would 
think  that  if  I  could — and  maybe  I  could  find  out  what  the  rate  was 
that  was  paid.  I  have  no  idea. 

Mr.  SCHAEFER.  OK. 

Mr.  Chairman,  I  think  I  am  finished. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman. 

Doctor,  I  have  been  looking  at  budget  requests  here.  The  total 
amount  of  your  grant  is  about  $7  million  for  the  assortment  of 
grants  that  you  received;  is  that  correct? 

Mr.  Fisher.  I  believe  so.  Maybe — no,  wait,  I  think  that  that  is 
for  the  treatment  trial. 

Mr.  Dingell.  Is  that  about  right? 

Mr.  Fisher.  Treatment,  yes. 

Mr.  Dingell.  Now,  in  your  requests  for  audit,  which  is  direct 
cost  support  for  audit  function  of  NSABP,  and  on  12-1-92  to  1-31- 
93,  the  original  request  was  for  $181,923,  the  review  committee 
recommended  $115,280;  then  the  final  NSABP  request  budget  was 


197 

$84,295,  so  it  was  cut  about  50  percent  or  thereabouts,  down  to 
$84,000. 

Now,  I  note  that  constitutes  about  1  percent  of  the  total  amount 
of  the  expenditures;  is  that  right? 

Mr.  Fisher.  I  don't  know. 

Mr.  DiNGELL.  If  I  understand  correctly,  that  would  be  one  audi- 
tor and  a  level  of  support  which  might  include  a  modest  but  not 
excessive  amount  of  travel  or  telephones  or  other  support,  and 
probably  no  clerical  assistance  or  support. 

Do  you  regard  that  as  being  an  adequate  level  of  audit  for  a  pro- 
gram of  this  magnitude? 

Mr.  Fisher.  No,  sir. 

Mr.  DiNGELL.  Now,  your  final  number,  then,  was  $84,295.  Now — 
so  that  was  the  final  request  that  was  made;  that  was  not  just — 
that  was  not  what  the  government  gave  you,  that  was  the  final  re- 
quest for  budget  support. 

Now,  who  was  it  that  made  that  request?  Was  that  you  or  was 
that  somebody  else? 

Mr.  Fisher.  Well,  the  $84,000  was  not  the  final  request,  sir. 

Mr.  DiNGELL.  It  says  here  on  the  paper  that  I  am  looking  at  that 
the  original  request,  it  says  original  NSABP  requested  direct  cost, 
then  review  recommendation  level,  and  then  the  next  column  says 
final  NSABP  request  budget.  So  that  is  the  request  that  was  sub- 
mitted, $84,295;  and  of  course  you  were  given  that,  so  you  cut  it 
that  much  before  you  ever  submitted  the  request. 

Who  was  it  that  cut  those  moneys?  Was  it  you  or  was  it  some- 
body else?  Did  you  request  it?  Who  requested  it? 

Mr.  Fisher.  Any  final  fiscal  sign-offs  were  done  by  me,  and  I  am 
just  not  clear  on  this. 

Mr.  DiNGELL.  I  am  not  criticizing  the  fact  that  you  had  a  party 
at  the  affair  that  year  that  amounted  to  $84,000,  but — well,  actu- 
ally $80,000,  but  it  does  seem  to  me  that  you  are  more  expansive 
with  your  expenditure  for  parties  than  you  are  with  your  auditing. 

Mr.  Fisher.  I  don't  believe  it  to  be  so,  sir.  I  would  hate  to  think 
that  I  would  be  so,  after  a  lifetime  of  dedication  to  science,  to  have 
thought  that  I  just  find  absolutely  devastating,  I  really  do.  I  don't 
think  that  I 

Mr.  DiNGELL.  Well,  all  I  can  say  here.  Doctor,  is  this,  that  ac- 
cording to  the  sheet  which  we  have,  which  is  a  statement  here  that 
was  submitted  to  the  committee,  it  says  the  final  NSABP  request 
budget  was  $84,295,  which  happens  to  be  exactly  the  amount  you 
got,  so  that  was  the  amount  you  requested.  That  is  for  an  entire 
year  of  auditing,  that  is  for  dealing  with  things  like  compliance,  ex- 
penditures of  money,  seeing  to  it  whether  appropriate  notice  is  sent 
out  with  regard  to  changes  in  risk  and  things  of  that  kind. 

Mr.  Fisher.  The  peer  review  committee  was  the  one  that  cut  us 
down,  the  review  recommended  level. 

Mr.  DiNGELL.  That  is  interesting  because  the  review  committee 
recommended  $115,280,  but  the  final  request  was  $84,000. 

Now,  who  cut  it  from  $115,000  to  $84,000?  That  is  a  cut  of 
$30,000;  that  is  a  cut  of  about  25  percent.  Now,  who  was  it  that 
cut  the  peer  review  committee's  recommendation?  Did  you  do  it? 
Did  somebody  else  do  it? 

Mr.  Fisher.  I  will  have  to  let  you  know,  sir.  I  can't  give  you 


198 

Mr.  DiNGELL.  Does  this  appear  to  have  been  a  wise  cut? 

Mr.  Fisher.  No. 

Mr.  DiNGELL.  Well,  Dr.  Fisher,  the  committee  thanks  you  for 
your  assistance  to  us. 

The  Chair  notes  there  is  a  vote  on  the  Floor.  I  am  going  to  run 
over  and  vote.  I  will  be  back  in  about  15  minutes,  and  the  commit- 
tee will  reconvene  then  in  15  minutes. 

[Brief  recess.  1 

Mr.  DiNGELL.  The  subcommittee  will  come  to  order.  The  Chair 
notes  that  our  next  witness  is  Samuel  Broder  M.D.,  Director,  Na- 
tional Cancer  Institute,  National  Institutes  of  Health. 

Dr.  Broder,  welcome  to  you.  Doctor,  you  are  aware  of  the  fact 
that  all  testimony  taken  before  this  committee  is  taken  under  oath. 
Do  you  have  any  objection  to  testifying  under  oath? 

Mr.  Broder.  I  understand. 

Mr.  DiNGELL.  Given  that  you  are  entitled  to  be  advised  by  coun- 
sel during  your  appearance,  do  you  desire  to  be  advised  by  counsel? 

Mr.  Broder.  Certainly  not. 

Mr.  DiNGELL.  You  will  note  that  copies  of  the  rules  of  the  com- 
mittee, the  subcommittee,  and  the  House  are  there  to  inform  you 
of  the  limitations  on  the  powers  of  the  subcommittee  as  well  as 
your  rights  as  you  appear  here  before  the  committee. 

If  you  have  no  objections,  then,  to  testifying  under  oath,  if  you 
will  please  raise  your  right  hand. 

[Witness  sworn.] 

Mr.  DiNGELL.  Doctor,  you  may  consider  yourself  under  oath.  Wel- 
come to  the  committee. 

TESTIMONY  OF  SAMUEL  BRODER,  DIRECTOR,  NATIONAL 

CANCER  INSTITUTE 

Mr.  Broder.  Good  afternoon.  Chairman  Dingell  and  members  of 
the  subcommittee.  I  am  Dr.  Samuel  Broder,  Director  of  the  Na- 
tional Cancer  Institute.  With  the  Chair's  permission,  I  would  like 
to  submit  my  full  written  remarks  for  the  record  and  briefly  give 
an  opening  statement. 

Mr.  DiNGELL.  Without  objection,  the  entirety  of  your  statement 
will  appear  in  the  record.  You  are  now  recognized  for  such  addi- 
tional comments  or  other  comments  as  you  choose. 

Mr.  Broder.  I  will  try  to  be  brief. 

I  am  pleased  to  have  this  opportunity  to  bring  you  up  to  date  on 
issues  discussed  at  the  April  13th  hearing  regarding  the  oversight 
and  management  of  clinical  research  conducted  by  the  National 
Surgical  Adjuvant  Breast  and  Bowel  Project,  referred  to  as  NSABP, 
whose  headquarters,  as  you  know,  is  at  the  University  of  Pitts- 
burgh and  also  to  bring  you  up  to  date  on  some  of  the  corrective 
actions  that  are  being  taken  to  address  the  problems  that  this  com- 
mittee has  identified  and  that  we  ourselves  have  identified. 

Please  allow  me  to  state  at  the  outset  that  progress  has  been 
made  over  the  past  few  weeks  in  coming  to  an  understanding  with 
officials  at  the  University  of  Pittsburgh  regarding  these  very  seri- 
ous issues.  This  is  reassuring  to  us  at  the  National  Cancer  Insti- 
tute, as  it  demonstrates  the  commitment  of  the  University  of  Pitts- 
burgh to  adhere  to  the  highest  ethical,  moral  and  scientific  stand- 


199 

ards.  We  particularly  acknowledge  Chancellor  O'Connor  and  Senior 
Vice  Chancellor  Detre,  as  well  as  Dr.  Ron  Herberman. 

This  commitment  has  led  to  certain  areas  of  agreement  that  we 
believe  will  begin  to  reestablish  the  public  trust  in  clinical  trials  in 
general  and  in  the  NSABP  in  particular. 

Specifically,  I  am  very  pleased  to  note  the  following: 

Accrual,  or  the  necessary  preludes  to  accrual  for  certain  key  clin- 
ical trials  has  resumed; 

New  procedures  are  in  place  at  NCI  to  deal  with  scientific  fraud 
or  misconduct,  especially  including  more  efficient  notification  to  the 
public; 

The  NSABP,  as  a  cooperative  group,  will  be  recompeted  through 
the  usual  peer  review  process; 

NSABP  is  in  the  process  of  selecting  new  scientific  leadership 
and  has  developed  a  corrective  action  plan  to  address  certain  prob- 
lems in  management  and  oversight. 

I  will  briefly  address  each  of  these  points. 

Clinical  trials  serve  as  one  of  the  foundation  stones  of  the  Na- 
tional Cancer  Program.  They  are  the  real  world  test  of  which  new 
therapies  or  preventive  measures  will  show  benefit  for  specific  pa- 
tients. The  components  of  all  clinical  trials  include  careful  and  sci- 
entifically appropriate  protocol  design,  informed  consent,  data  man- 
agement control,  and  publication  of  trial  results.  We  must  have  all 
of  these  functioning  together. 

The  disclosures  of  data  irregularities  in  NSABP  trials  and  the 
lapses  of  oversight  at  NSABP  headquarters  in  auditing  and  report- 
ing trials,  including  NCI's  participation  in  these  matters  and  in 
publishing  reanalyses  of  the  affected  studies  with  clear  disclosure 
to  the  reader,  raise  serious  questions  regarding  the  ability  of 
NSABP  to  perform  clinical  research.  In  our  system  of  cancer  re- 
search, the  primary  responsibility  for  the  conduct  of  clinical  trials 
must  rest  with  the  grantee,  but  the  National  Cancer  Institute  has 
responsibilities  as  well. 

To  do  its  job  more  effectively,  NCI  has  established  a  new  branch 
to  oversee  the  quality  assurance  aspects  of  its  clinical  trials,  and 
I  can  provide  more  details.  We  have  provided  more  explicit  guide- 
lines for  auditing  and  for  dealing  with  irregularities  in  clinical 
trials  and  NCI  has  undertaken  a  reevaluation  of  its  quality  assur- 
ance program  and  is  moving  to  strengthen  key  comiponents. 

As  for  NSABP  and  its  leadership,  the  group  has  submitted  a  cor- 
rective plan,  including  provisions  for  on-site  oversight  by  NCI  staff. 
We  have  found  this  plan  for  resuming  certain  clinical  trials  to  be 
generally  acceptable,  subject  to  some  clarification  or  modification 
and  certainly  subject  to  continuing  oversight.  Moreover,  all  parties, 
including  the  University  of  Pittsburgh,  are  committed  to  allowing 
the  peer  review  process  to  determine  the  future  location  and  sci- 
entific direction  of  its  clinical  trials  administration. 

Two  of  our  advisory  boards,  the  Division  of  Cancer  Prevention 
and  Control  Board  of  Scientific  Counselors  and  the  National  Can- 
cer Advisory  Board,  both  recommended  in  formal  votes  that  accrual 
for  new  patients  for  the  Breast  Cancer  Prevention  Trial  with 
tamoxifen  be  resumed  as  soon  as  possible.  In  addition,  on  June  7, 
1994,  the  Oncologic  Drugs  Advisory  Committee  of  the  Food  and 
Drug  Administration  reviewed  the  recent  information   regarding 


200 

endometrial  cancer  deaths  and  other  information  and  concluded  the 
tamoxifen  Breast  Cancer  Prevention  Trial  should  continue,  and 
also  recommended  that  accrual  be  resumed. 

Unlike  most  treatment  trials,  the  prevention  trial  requires  risk 
assessment  as  the  first  step,  but  risk  assessment  does  not  mean  an 
immediate  assignment  to  either  placebo  or  tamoxifen,  as  the  proc- 
ess requires  roughly  one  month's  lead  time.  In  general,  resumption 
of  accrual  and  risk  assessments  will  be  allowed  at  NCI-designated 
cancer  centers,  formal  members  of  our  Community  Clinical  Oncol- 
ogy Program — the  so-called  CCOP's,  which  are  different  from 
NSABP — and  in  the  case  of  NSABP  members,  certain  institutions 
with  an  acceptable  audit  record  in  the  past  3  years. 

I  will  not  review  the  entire  history  of  the  events  that  have  led 
us  to  this  point,  as  many  issues  have  been  addressed  in  previous 
testimony.  I  would  like  to  bring  to  your  attention  several  additional 
irregularities  that  have  been  identified  at  a  few  participating 
NSABP  institutions.  The  problems  range  from  incomplete  record- 
keeping to  deficient  informed  consent  procedures.  Following  that,  I 
would  be  grateful  for  permission  to  highlight  a  few  of  the  main 
facts  and  steps  that  we  have  taken  to  strengthen  some  of  our  pro- 
cedures. 

At  the  last  hearing,  we  informed  you  about  the  issue  of  serious 
data  irregularities  at  St.  Mary's  Hospital  in  Montreal.  The  problem 
had  been  noted  by  NSABP  in  September  of  1993,  but  was  not 
brought  to  NCI's  attention.  In  fact,  NCI  staff  independently  discov- 
ered the  documentation  regarding  this  problem  in  March  of  1994 
during  our  site  visit  to  NSABP  headquarters.  Currently,  the  Office 
of  Research  Integrity  is  still  investigating  this  institution,  but  I  be- 
lieve that  there  are  data  falsifications  involved. 

Another  of  the  institutions  is  the  Memorial  Cancer  Research 
Foundation  in  Los  Angeles,  where  NCI  conducted  an  audit  on  April 
29th  and  30th  at  the  request  of  the  local  principal  investigator,  fol- 
lowing contact  by  a  news  reporter.  Files  for  NSABP  patients  en- 
rolled on  the  B-06  study  of  breast-sparing  surgery  and  those  of 
other  patients  were  reviewed  by  the  NCI  auditors.  The  major  areas 
of  concern  noted  by  the  NCI  auditors  included  patient  eligibility, 
the  randomization  process  and  the  obtaining  of  informed  consent. 

These  findings  confirmed  the  findings  of  the  NSABP's  own  audit 
report  of  1990  that  a  serious  problem  had  been  identified  regarding 
the  accuracy  of  the  data  reported  at  randomization. 

It  is  of  note  that  neither  the  investigator  in  Los  Angeles  nor  the 
National  Cancer  Institute  had  been  notified  of  the  concerns  identi- 
fied in  the  1990  NSABP  audit  report,  nor  had  there  been  any  fol- 
low-up action  by  NSABP  to  correct  these  problems.  We  have  been 
informed  that  the  NSABP  report,  in  fact,  languished  in  obscurity 
in  an  unmailed  envelope  in  the  NSABP  files.  Correspondence  from 
NSABP  provided  to  the  auditors  appeared  to  or  actually  did  con- 
gratulate the  principal  investigator  in  Los  Angeles  on  the  status  of 
follow-up  cases.  This  is  incomprehensible  to  us. 

This  matter  has  been  referred  to  the  Office  for  Protection  from 
Research  Risks,  OPRR,  and  the  local  Institutional  Review  Board, 
which  we  abbreviate  as  IRB,  because  of  concerns  about  possible 
breaches  of  patient  confidentiality  and  patients  not  having  been 
provided,  or  not  having  been  given  an  opportunity  to  provide  a 


201 

truly  informed  consent;  and  to  ORI,  for  issues  related  to  the  sci- 
entific conduct  of  the  trial. 

Other  problems  include  South  Nassau  Hospital  on  Long  Island, 
where  patients  were  enrolled  despite  questionable  eligibility.  NCI 
had  been  given  verbal  notification  that  the  NSABP  had  suspended 
the  institution  in  follow-up  to  the  audit  report.  However,  from  what 
we  can  tell,  this  was  never  done  and  none  of  the  additional  follow- 
up  reports  were  provided  to  us. 

I  want  to  echo  Chancellor  O'Connor's  comments  that  you  heard 
earlier  regarding  the  important  contributions  of  this  committee's 
staff  in  helping  us  identify  and  sort  through  these  very  complex  is- 
sues. 

Other  NSABP  audit  sites  such  as  Tulane  and  Louisiana  State 
University  demonstrated  certain  data  management  deficiencies. 
NCI  has  conducted  two  audits  at  each  of  these  sites.  At  the  initial 
audits,  which  were  arranged  with  essentially  no  advance  notice, 
there  were  substantial  portions  of  missing  data  on  eligibility  and 
other  matters,  perhaps  due  in  part  to  the  shortness  of  the  notice; 
but  in  all  measures,  this  was  an  unacceptable  site  visit  situation. 

Both  institutions  have  developed  new  data  management  plans 
and  have  taken  corrective  actions  to  ensure  that  these  kinds  of 
problems  are  minimized  or  don't  occur  in  the  future.  In  the  case  of 
Tulane,  we  have  tentatively  agreed  on  a  conditional  resumption  of 
accrual  based  on  their  recruitment  of  a  new  leader  for  clinical 
trials,  the  development  of  a  comprehensive  data  management  sys- 
tem, and  also  provided  that  they  expeditiously  clear  up  outstanding 
delinquent  data  and  residual  issues  from  the  May  1994  audit.  They 
must  also  make  adequate  provisions  to  ensure  the  performance  of 
their  affiliates,  and  they  must  agree  and  have  agreed  to  a  reaudit 
in  roughly  6  months. 

We  hope  that  a  similar  plan  can  be  worked  out  for  Louisiana 
State  University. 

The  NSABP  uses  as  its  testing  ground  real  surgeons,  the  kind  of 
individual  seen  by  the  average  American  when  they  seek  treatment 
for  cancer.  However,  this  characteristic,  which  is  a  virtue  in  many 
ways,  can  also  pose  special  challenges  for  adhering  to  data  manage- 
ment and  reporting  requirements. 

For  our  part,  NCI  requested  changes  in  NSABP  audit  proce- 
dures, including  on-site  auditing,  auditing  more  patient  charts  and 
providing  to  NCI  fixed  annual  audit  schedules  long  before  these  is- 
sues had  become  front  page  news.  Unfortunately,  NSABP  did  not 
comply,  and  NCI  staff  did  not  take  action  to  compel  compliance. 

Regrettably,  our  staff  routinely  accepted  late  reports  from 
NSABP  with  their  promissory  notes  to  do  better  in  the  future,  or 
with  their  explanation  that  the  responsibility  for  conducting  high- 
priority  studies  had  strained  their  ability  to  issue  timely  reports, 
or  sometimes  with  no  explanation.  This  will  not  happen  again. 

The  NSABP  probation  period  requires  submission  of  an  audit 
schedule  for  the  coming  month,  the  performance  of  on-site  audits 
and  the  auditing  of  10  percent  of  all  charts.  Timely  reporting  is  re- 
quired; I  believe  we  have  their  attention.  An  electronic  system  for 
alerting  NCI  staff  to  expect  and  to  review  site  visit  reports  for  all 
cooperative  groups  is  being  established. 


202 

I  would  like  to  very  briefly  turn  to  one  other  area.  As  of  June 
10,  1994,  287  of  293  Institutional  Review  Boards  have  reviewed 
and  approved  the  revised  protocol  and  consent  form,  and  approxi- 
mately 3,000  patients  have  signed  the  revised  consent  in  connec- 
tion with  the  tamoxifen  studies  that  we  have  discussed  earlier. 
There  is  a  "Dear  Participant"  letter  that  was  targeted  to  all  women 
and  was  required  as  of  April  of  1994;  and  we  will  explore  other 
ways  of  communicating  directly  with  the  women  in  our  studies. 

Finally,  we  have  initiated  recovery  of  funds  in  instances  where 
scientific  fraud  or  misconduct  was  identified.  Recovery  of  funds  in 
cases  of  a  finding  of  scientific  fraud  or  misconduct  is  now  standard 
operating  procedure  at  the  National  Cancer  Institute  and  is  one  of 
the  action  items  in  our  manual  issuance  on  this  topic. 

Also,  the  University  of  Pittsburgh  has  been  instructed  to  provide 
criteria  for  ineligible  or  inevaluable  patient  accrual  that  would  be 
subject  to  reimbursement  under  a  condition  of  the  grant  that  has 
been  in  place  since  April  of  1993 — again,  before  these  issues  be- 
came newspaper  items. 

Mr.  Chairman,  this  has  been  a  very  difficult  time  for  everyone 
involved  in  the  events  that  have  occurred  over  the  past  few 
months.  There  has  been  much  criticism  of  all  parties  involved  and 
much  concern  about  the  future.  We  have  listened  carefully  to  these 
comments  and  will  do  our  best  to  address  them.  All  of  us,  espe- 
cially those  in  the  scientific  community,  must  keep  in  mind  that 
the  uncertainties  and  challenges  we  face  in  these  matters  amount 
to  nothing  compared  to  what  the  average  cancer  patient  must  face. 

Cancer  patients  and  their  loved  ones  are  our  constituency. 

Thank  you  for  the  opportunity  to  appear  before  you  today. 

[The  prepared  statement  of  Dr.  Broder  follows:] 


203 


Statement  of  Samuel  Broder,  M.D. 


Good  morning,  Chairman  Dingell  and  members  of  the  Subcommittee.    I  am  Dr.  Samuel 
Broder,  Director  of  the  National  Cancer  Institute.    With  me  today  are  Dr.  Bruce  Chabner, 
Director  of  the  Division  of  Cancer  Treatment,  Dr.  Michaele  Christian,  Acting  Chief  of  the 
Clinical  Trials  Monitoring  Branch,  DCT,  and  Dr.  Leslie  Ford,  Acting  Deputy  Director  of  the 
Division  of  Cancer  I*revention  and  Control,  NCI.    I  am  pleased  to  have  this  opportunity  to 
bring  you  up  to  date  on  issues  discussed  at  the  April  13  hearing  regarding  the  oversight  and 
management  of  clinical  research  conducted  by  the  National  Surgical  Adjuvant  Breast  and 
Bowel  Project  (NSABP),  whose  headquarters  is  at  the  University  of  Pittsburgh,  and  the 
corrective  actions  that  are  being  taken  to  address  these  problems. 

Please  allow  me  to  state  at  the  outset  that  progress  has  been  made  over  the  past  few  weeks  in 
coming  to  an  understanding  with  officials  at  the  University  of  Pittsburgh  regarding  these  very 
serious  issues.    This  is  most  reassuring  to  us  at  NCI,  as  it  demonstrates  the  commitment  of 
the  University  of  Pittsburgh  to  adhere  to  the  highest  ethical,  moral,  and  scientific  standards. 
We  particularly  acknowledge  Chancellor  O'Connor  and  Senior  Vice-Chancellor  Detre,  as 
well  as  Dr.  Ron  Herberman.   This  commitment  has  led  to  certain  areas  of  agreement  that  we 
believe  will  begin  to  re-establish  the  public  trust  in  the  clinical  trials  process  of  the  NSABP. 

Specifically,  I  am  pleased  to  note  the  following: 

1.  Accrual  for  certain  key  clinical  trials  has  resumed; 

2.  New  procedures  are  in  place  at  NCI  to  deal  with  scientific  fraud  or  misconduct; 

3.  The  NSABP,  as  a  cooperative  group,  will  be  recompeted  through  the  usual  peer 
review  process; 

4.  NSABP  is  in  the  process  of  selecting  new  scientific  leadership  and  has  developed  a 
corrective  action  plan  to  address  problems  in  management  and  oversight. 

I  will  address  each  of  these  points  in  greater  detail. 

Clinical  trials  serve  as  one  of  the  foundation  stones  of  the  National  Cancer  Program.   They 
are  the  real-world  test  of  which  new  therapies  (or  preventive  measures)  will  show  benefit  for 
specific  patients.    The  key  components  of  all  clinical  trials  include  careful  and  scientifically 
appropriate  protocol  design,  informed  consent,  data  management,  quality  control,  and 
publication  of  trial  results  based  on  thorough  statistical  analysis.    When  all  of  these 
components  are  in  place  and  functioning  smoothly,  we  can  have  confidence  in  the  results  of 
clinical  trials.    When  one  or  more  of  these  components  breaks  down,  we  must  identify  the 
problem  as  quickly  as  possible  and  take  action  to  repair  it.   The  disclosures  of  data 
irregularities  in  NSABP  trials  and  the  lapses  of  oversight  at  NSABP  headquarters  in  auditing 
and  reporting  trials,  and  in  publishing  reanalyses  of  the  affected  studies  with  clear  disclosure 
to  the  reader,  raised  serious  questions  regarding  the  ability  of  NSABP  to  produce  valid 
research.   The  primary  responsibility  for  the  conduct  of  clinical  trials  must  rest  with  the 
grantee.    But  NCI  has  responsibilities  as  well. 


204 


To  do  its  job  more  effectively,  NCI  has  established  "  new  Branch  to  oversee  the  quality 
assurance  aspects  of  its  large-scale  clinical  trials.    More  explicit  guidelines  for  auditing  and 
for  dealing  with  data  irregularities  in  clinical  trials  have  been  set  in  place,  and  NCI  has 
undertaken  a  re-evaluation  of  its  quality  assurance  program  and  is  moving  to  strengthen  key 
components.    As  for  the  NSABP  and  its  leadership,  the  group  has  submitted  a  corrective  plan 
of  action,  including  provisions  for  on-site  oversight  by  NCI  staff.    NCI  has  found  this  plan 
for  resuming  trials  to  be  generally  acceptable  subject  to  some  clarification  or  modification  and 
continuing  oversight.    Moreover,  all  parties-including  the  University  of  Pittsburgh— are 
committed  to  allowing  the  peer  review  process  to  determine  the  future  location  and  scientific 
direction  of  its  clinical  trials  administration. 

Accrual  has  been  opened  at  selected  sites  to  certain  key  clinical  trials.    For  selected  treatment 
trials  in  breast  cancer  and  rectal  cancer,  this  means  patients  may  be  entered  into  trials 
immediately.   Two  of  our  advisory  twards,  the  Division  of  Cancer  Prevention  and  Control 
Board  of  Scientific  Counselors  and  the  National  Cancer  Advisory  Board,  both  recommended 
in  formal  votes  that  accrual  for  new  patients  for  the  Breast  Cancer  Prevention  Trial  with 
tamoxifen  be  resumed  as  soon  as  possible.    In  addition,  on  June  7,  1994,  the  Oncologic 
Drugs  Advisory  Committee  of  the  Food  and  Drug  Administration  reviewed  the  recent 
information  regarding  endometrial  cancer  deaths  and  other  information  and  concluded  that  the 
tamoxifen  Breast  Cancer  Prevention  Trial  should  continue,  and  recommended  that  accrual  be 
resumed.    Unlike  most  treatment  trials,  the  BCPT  requires  risk-assessment  as  the  first  step, 
but  risk  assessment  does  not  mean  an  immediate  assignment  to  receive  either  placebo  or 
tamoxifen,  as  the  process  requires  at  least  one  month's  lead  time.    In  general,  resumption  of 
accrual  and  risk  assessments  will  be  allowed  at  NCI-designated  Cancer  Centers,  formal 
members  of  the  Community  Clinical  Oncology  Program  (CCOPs),  and  in  the  case  of  NSABP 
members,  certain  institutions  with  an  acceptable  audit  record  in  the  past  three  years. 

Currently  NSABP  is  in  the  process  of  choosing  new  scientific  leadership  and  has  informed  us 
that  they  hope  to  complete  that  process  by  September  1,  1994.    As  you  know.  Dr.  Ron 
Herberman  has  been  acting  as  the  interim  chairman  of  NSABP.    Once  the  new  leadership  is 
in  place,  we  hope  to  allow  roughly  one  year  to  permit  all  potential  grantee-competitors  to 
prepare  grant  applications  for  components  related  to  statistical  support,  auditing,  etc.,  and 
submit  them  for  peer  review. 

With  your  permission,  I  will  not  review  the  entire  history  of  the  events  that  have  led  us  to 
this  point  as  many  issues  have  been  addressed  in  previous  testimony;  however,  I  would  like 
to  bring  to  your  attention  several  additional  irregularities  that  have  been  identified  at  a  few 
participating  NSABP  institutions.   The  problems  range  from  incomplete  record-keeping  to 
deficient  informed  consent  procedures.    Following  that,  I  would  like  to  highlight  a  few  of  the 
main  facts  and  the  steps  we  have  taken  to  strengthen  some  of  our  procedures. 

At  the  last  hearing,  we  informed  you  about  the  issue  of  serious  data  irregularities  at  St. 
Mary's  Hospital  in  Montreal.   The  problem  had  been  noted  by  NSABP  in  September  1993 
but  was  not  brought  to  NCI's  attention.    In  fact,  NCI  staff  independently  discovered  the 


205 


documentation  regarding  this  problem  in  March  1994  during  our  site  visit  to  NSABP 
headquarters.    Currently  the  Office  of  Research  Integrity  (ORI)  is  still  investigating  this 
incident. 

Another  of  the  institutions  is  the  Memorial  Cancer  Research  Foundation  in  Los  Angeles, 
California,  where  NCI  conducted  an  audit  on  April  29-30,  at  the  request  of  the  local 
Principal  Investigator  following  contact  by  a  news  reporter.    An  NSABP  audit  of  this 
institution  had  been  conducted  and  a  report  prepared  on  April  3,  1990;  however,  apparently 
neither  the  Principal  Investigator  in  Los  Angeles  nor  NCI  had  been  provided  with  a  copy  of 
the  report,  which  identified  several  inconsistencies  and  incomplete  records.    Files  for  NSABP 
patients  enrolled  on  the  B-06  study  of  breast-sparing  surgery,  and  those  of  other  patients, 
were  reviewed  by  the  NCI  auditors.   The  major  areas  of  concern  noted  by  the  NCI  auditors 
included  patient  eligibility,  the  randomization  process,  and  the  obtaining  of  informed  consent. 
These  findings  confirmed  the  findings  of  the  NSABP's  own  audit  report  of  1990  that  a 
serious  problem  had  been  identified  regarding  the  accuracy  of  the  data  reported  at 
randomization. 

Neither  the  investigator  in  Los  Angeles  nor  NCI  had  been  notified  of  the  concerns  identified 
in  the  1990  NSABP  audit  report,  nor  had  there  been  any  follow-up  action  by  NSABP  to 
correct  these  problems.    We  have  been  informed  that  the  NSABP  report  was  attached  to  an 
unmailed  envelope  in  the  NSABP  files.   In  fact,  correspondence  from  NSABP  provided  to 
the  auditors  congratulated  the  Principal  Investigator  on  the  status  of  follow-up  cases.   This 
matter  has  been  referred  to  the  Office  for  Protection  from  Research  Risks  (OPRR)  and  the 
local  Institutional  Review  Board  (IRB)  because  of  concerns  about  possible  breaches  of  patient 
confidentiality  and  patients  not  having  provided  informed  consent,  and  to  ORI  due  to  issues 
related  to  the  scientific  conduct  of  the  trial. 

Other  problems  include  South  Nassau  Hospital  on  Long  Island  where  two  patients  were 
enrolled  despite  questionable  ehgibility.   NCI  had  been  given  verbal  notification  that  NSABP 
had  suspended  the  institution  in  follow-up  to  the  audit  report;  however,  this  was  apparently 
never  done  and  none  of  the  additional  follow-up  reports  were  provided  to  us.  [Perhaps  I 
could  take  this  opportunity  to  acknowledge  the  diligence  and  effectiveness  of  your  staff  in 
helping  us  identify  and  sort  through  these  issues.] 

Other  NSABP  audit  sites  such  as  Tulane  and  Louisiana  State  University  demonstrated  certain 
data  management  deficiencies.    NCI  has  conducted  two  audits  at  each  of  these  sites.    At  the 
initial  audits,  which  were  arranged  with  no  advance  notice,  there  were  large  amounts  of 
missing  data  on  eligibility  and  other  matters  due  in  part  to  unavailable  charts.   When  we 
returned  in  May  after  more  notice,  the  majority  of  charts  and  missing  data  had  been  located 
and  were  available  for  review.    In  addition,  both  institutions  have  developed  new  data 
management  plans  and  taken  corrective  actions  to  ensure  that  these  kinds  of  problems  don't 
occur  in  the  ftiture.   We  have  tentatively  agreed  to  a  conditional  resumption  of  accrual  at 
Tulane,  which  developed  a  comprehensive  data  management  system,  providing  that  they: 
expeditiously  clear  up  outstanding  delinquent  data  and  residual  issues  from  the  May  1994 


206 


audit;  make  adequate  provisions  to  ensure  the  performance  of  their  affiliates;  and  agree  to  a 
reaudit  in  six  months.    We  hope  that  a  similar  plan  can  be  worked  out  for  LSU  once  we  have 
received  additional  details  regarding  their  corrective  plan. 

One  of  the  difficulties  we  faced  was  that  NSABP,  one  of  nine  major  clinical  trials  cooperative 
groups,  had  a  philosophy  of  using  a  less  stringent  auditing  system  than  the  other  groups. 
This  was  due  to  several  factors,  including  the  very  large,  community-based  surgical 
membership  of  NSABP,  its  long  history  of  productivity,  its  proud  reputation,  and  its  insistent 
adherence  to  its  own  traditions  for  auditing  and  quality  control.   The  community-based  nature 
of  NSABP  surgeon  participants  is  one  of  the  group's  greatest  strengths:   Their  results  reflect 
the  ability  of  community-based  surgeons  to  apply  new  treatments  and  new  surgical  methods. 
The  NSABP  uses  as  its  testing  ground  the  real  doctors  who  the  average  American  will  see 
when  seeking  treatment.    However,  this  same  characteristic  also  can  pose  special  challenges 
for  adhering  to  data  management  and  reporting  requirements. 

For  our  part,  NCI  requested  changes  in  NSABP  audit  procedures  including  on-site  auditing, 
auditing  more  patient  charts,  and  providing  to  NCI  an  annual  audit  schedule.    Unfortunately, 
NSABP  did  not  comply  and  NCI  staff  did  not  take  action  to  compel  compliance. 
Regrettably,  our  staff  routinely  accepted  late  reports  from  NSABP  with  their  explanation  that 
the  responsibility  for  conducting  high  priority  studies  had  strained  their  ability  to  issue  timely 
reports,  or  sometimes  with  no  explanation.   This  will  no  longer  happen.   The  NSABP 
probation  period  requires  submission  of  an  audit  schedule  for  the  coming  month,  the 
performance  of  on-site  audits,  and  the  auditing  of  ten  percent  of  all  charts.    Timely  reporting 
is  required.    An  electronic  system  for  alerting  NCI  staff  to  expect  and  to  review  site  visit 
reports  for  all  cooperative  groups  is  being  established  and  will  be  operational  within  90  days. 
In  addition,  we  have  met  with  the  Clinical  Cooperative  Group  chairmen,  who  have  agreed 
that  there  should  be  common  standards  for  all  groups  in  terms  of  what  constitutes  an 
acceptable  audit.   These  criteria  are  being  ''sveloped  in  conjunction  with  the  groups  and  wiU 
be  incorporated  into  the  new  NCI  on-site  monitoring  guidelines.    Adherence  to  these  criteria 
is  included  in  the  terms  of  award  for  all  cooperative  group  grantees.    1  should  point  out  that 
these  will  represent  minimum  criteria,  and  individual  Groups  would  certainly  have  the  option 
to  impose  additional  (more  stringent)  requirements  for  their  member  institutions. 

There  will  also  be  cooperative  group-wide  standards  for  auditing,  reporting  audit  results,  and 
dealing  with  instances  of  fraud  or  misconduct,  as  well  as  a  group-wide  requirement  for  ethics 
training  and  for  credentialing  new  investigators. 

We  have  met  with  officials  from  the  group  and  from  the  University  of  Pittsburgh  to  discuss 
how  the  remaining  problems  can  be  addressed.    Several  specific  items  have  been  discussed 
and  agreements  reached  between  NCI  and  the  University  of  Pittsburgh: 

o  We  are  informed  that  NSABP  accepts  the  idea  that  its  management  needs  improve- 
ment, and  the  Chancellor  of  the  University  of  Pittsburgh  has  issued  an  apology  for 
that  institution's  role  in  these  problems; 


207 


o         The  University  of  Pittsburgh  will  resolve  the  inconsistency  found  as  a  result  of  the 
EMMES  reanalysis  of  the  B-06  (breast-sparing  surgery)  study  between  data  and 
published  journal  articles  regarding  ipsilateral  recurrence  of  breast  cancer  (i.e. 
recurrence  in  the  same  breast); 

o         Each  week,  NCI  staff  will  be  on-site  at  NSABP  headquarters  in  Pittsburgh  to  enhance 
cooperation  efforts  and  to  provide  oversight.   Pittsburgh  will  provide  appropriate 
space; 

o         NCI  has  raised  concerns  regarding  remaining  problematic  issues,  including  a  1993 
memorandum  from  Dr.  Carol  Redmond  to  Dr.  Bernard  Fisher  noting  her  serious 
concerns  about  protocol  design  and  informed  consents,  and  we  expect  a  response  from 
NSABP;  and 

0  The  University  is  proceeding  with  a  broad  inquiry  into  NSABP  administrative  issues, 
data  irregularities,  and  human  subjects  protection  in  coordination  with  the  Office  of 
Research  Integrity  and  the  Office  for  Protection  from  Research  Risks. 

The  NCI  is  committed  to  working  with  the  University  of  Pittsburgh  and  the  new  leadership  of 
NSABP  to  ensure  that  research  continues  under  careftil  and  appropriate  scientific  and 
administrative  oversight.    We  believe  that  the  leadership  of  the  NSABP  should  be  given  an 
opportunity  to  heal  any  remsiining  wounds,  galvanize  the  membership,  and  develop  and 
implement  a  scientific  agenda.    It  is  possible  that  there  would  be  a  physical  relocation  of  the 
operations  and  statistical  offices  to  new  institutions  and  new  sites.   The  operations  offices  of 
other  cooperative  groups  have  relocated  in  the  past,  and  there  are  precedents  for  having  the 
chair  and  the  statistical  center  located  at  different  sites.   If  this  were  to  happen,  the  NCI  on- 
site  presence  at  the  University  of  Pittsburgh  would  help  expedite  the  process.    But,  once 
again,  we  are  committed  to  allowing  the  principles  of  open  competition  and  peer  review  to 
resolve  these  kinds  of  issues. 

We  are  still  in  the  process  of  conducting  a  detailed  audit  of  the  B-06  (breast-sparing)  study. 
Institutions  that  contributed  10  or  more  patients  to  the  B-06  study,  which  accounts  for 
approximately  1500  patients,  will  have  been  audited  most  likely  by  August.   An  NCI 
contractor  will  then  conduct  an  independent  statistical  reanalysis.   We  estimate  that  this  re- 
analysis  will  be  completed  by  late  summer  or  early  fall,  but  I  cannot  absolutely  promise  this 
as  a  deadline. 

NCI  staff  are  coordinating  certain  activities  with  the  DHHS  Office  of  the  Inspector  General. 
This  will  likely  include  reviews  that  will  compare  the  research  records  at  the  NSABP 
statistical  center  with  the  computerized  database  used  to  analyze  the  study  to  ensure  no  errors 
or  bias  were  introduced  at  the  statistical  center. 

1  would  like  to  return  briefly  to  the  Breast  Cancer  Prevention  Trial.   One  of  the  criticisms  of 
this  trial  has  been  the  lack  of  completeness  and  promptness  of  the  informed  consent  process. 


208 


NCI  has  an  obligation  to  provide  accurate,  up-to-date  scientific  information  to  patients  who 
participate  in  our  studies.    We  have  taken  some  steps  to  quicken  the  process  and  we  are 
exploring  other  new  ways  of  communicating  directly  with  patients  to  inform  them  of  changes 
to  informed  consent.    On  April  18,  as  instructed  by  NCI,  NSABP  sent  a  notification  to  all 
participating  sites  that  they  must  convey  a  "Dear  Participant"  letter  to  all  BCPT  participants 
by  April  22,  1994.   This  step  was  intended  to  ensure  that  all  women  participating  in  the 
BCPT  would  have  immediate  notification  regarding  the  information  that  had  been  distributed 
to  the  participating  centers  in  January  1994.    We  felt  this  was  necessary  because  the  usual  and 
customary  process  being  followed,  including  review  and  approval  by  the  local  IRBs,  is  a 
lengthy  one  and  many  women  had  not  been  contacted  directly.   The  information  provided  to 
women  in  the  "Dear  Participant"  letter  was  the  same  as  that  included  in  the  Zeneca  "Dear 
Doctor"  letter  dated  April  8,  1994.    In  addition  to  requiring  direct  notification  to  participants, 
we  also  are  monitoring  the  reconsenting  process  very  closely.    Following  instructions  issued 
by  the  Office  from  Protection  of  Research  Risks  in  November  1992,  each  IRB  was  provided 
with  the  full  NSABP  protocol  and  consent  form,  as  well  as  the  local  institutions's  version  of 
the  consent  form. 

As  of  June  10,  1994,  287  out  of  293  institutional  IRBs  have  reviewed  and  approved  the 
revised  protocol  and  consent  form,  and  2,957  patients  have  signed  the  revised  consent  form. 
As  I  mentioned  a  few  moments  ago,  however,  aU  women  participating  in  the  trial  were 
targeted  to  receive  notice  of  the  changes  as  of  April  22,  1994. 

We  will  continue  to  explore  novel  ways  of  communicating  new  information  to  patients 
quickly.    One  approach  we  are  testing  involves  an  electronic  bulletin  board  that  may  be 
available  in  some  doctors'  offices  or  participating  hospitals  where  patients  could  browse 
through  information  updates  or  even  electronically  indicate  their  "re-consent"  after  having 
read  new  information  and  discussed  it  with  appropriate  medical  staff.    We  will  explore  many 
options  to  make  more  information  available  to  patients  more  rapidly,  and  no  single  method  is 
likely  to  serve  all  of  our  needs. 

Finally,  we  have  initiated  recovery  of  funds  in  instances  where  scientific  fraud  or  misconduct 
was  identified.    Recovery  of  funds  in  cases  of  a  finding  of  scientific  fraud  or  misconduct  is 
now  standard  operating  procedure  at  the  National  Cancer  Institute  and  is  one  of  the  action 
items  in  our  manual  issuance  on  this  topic.    Also,  the  University  of  Pittsburgh  has  been 
instructed  to  provide  criteria  for  ineligible  or  inevaluable  patient  accrual  that  would  be  subject 
to  reimbursement  under  a  condition  of  the  grant  award  that  has  been  in  place  since  April, 
1993. 

Mr.  Chairman,  this  has  been  a  very  difficult  time  for  everyone  involved  in  the  events  that 
have  occurred  over  the  past  few  months.   There  has  been  much  criticism  of  all  parties 
involved  and  much  concern  about  the  future.    We  have  listened  carefully  to  these  comments 
and  will  do  our  best  to  address  them.    In  this  process,  our  advisory  groups  have  been  most 
helpful.    All  of  us,  especially  those  in  the  scientific  community,  must  keep  in  mind  that  the 
uncertainties  and  challenges  we  face  in  these  matters,  amount  to  nothing  compared  to  what 
the  average  cancer  patient  must  face.    Cancer  patients  and  their  loved  ones  are  our 
constituency.    I  believe  that  the  result  will  be  a  stronger  and  more  responsive  clinical 
cooperative  group  program  made  up  of  dedicated,  caring,  principled  scientists  and  physicians. 
We  must  expect  nothing  less. 

Thank  you  for  this  opportunity  to  appear  before  you  today. 


209 

Mr.  DiNGELL.  Dr.  Broder,  the  committee  thanks  you  for  your  very 
helpful  testimony. 

The  Chair  recognizes  now  my  good  friend  from  Colorado  for  such 
questions  as  he  chooses. 

Mr.  SCHAEFER.  Thank  you,  Mr.  Chairman. 

Dr.  Broder,  the  tamoxifen  trials  have  been  resumed,  as  I  under- 
stand it.  Do  you  believe  that  NSABP  is  capable  of  monitoring  these 
trials  at  the  present  time? 

Mr.  Broder.  Yes,  I  do.  We  will  have  oversight  and  we  will  have 
an  individual  up  there  a  certain  portion  of  the  time,  physically  on 
site.  They  have  provided  us  or  have  assured  us  that  there  will  be 
space,  and  we  believe  that  they — based  on  a  number  of  things  that 
they  presented  to  us  privately  and  in  some  of  the  testimony  that 
you  have  heard — have  a  sincere  commitment  to  this  issue,  and  I 
believe  that  they  have  a  can-do  spirit  and  they  will  comply  with  us 
and  comply  with  the  needs  of  the  public  and  with  the  interests  of 
the  Congress. 

Mr.  SCHAEFER.  I  am  sure  that  this  committee,  as  well  as  a  lot 
of  the  people  in  this  country,  agree  that  they  have  a  new  spirit, 
that  we  aren't  going  to  get  into  the  same  problems  all  over  again. 
What  type  of  person  are  you  going  to  have  up  there?  Are  you  going 
to  have  a  physician  there  or  a  doctor? 

Mr.  Broder.  We  will  try  to  have  a  professional  full-time  em- 
ployee of  the  National  Cancer  Institute  up  there  a  certain  amount 
of  time.  I  can't  tell  you  the  individual  will  be  there  7  days  a  week, 
24  hours  a  day,  but  there  will  be  an  individual  up  there,  and  we 
will  probably  have  a  certain  schedule  or  rotation  since  we,  at  the 
current  time,  cannot  detail  a  single  individual. 

We  will  probably  establish  a  rotation  to  have  an  NCI  professional 
on  site  periodically  to  oversee  and  to  interact  and  to  make  sure 
that  we  are  in  full  compliance  with  all  of  the  issues,  and  that  we 
are  correcting  the  problems  that  have  been  identified. 

Mr.  SCHAEFER.  In  your  opinion,  does  NSABP  currently  have  ca- 
pabilities to  conduct  their  audits  and  generate  audit  reports  that 
change  that  much  that  they  can  do  that  now? 

Mr.  Broder.  Thank  you  for  the  question,  Mr.  Schaefer. 

I  want  to  make  a  point  very  briefly  that  while  there  are  going 
to  be  some  exceptions  to  what  I  am  going  to  say,  many  of  the  issues 
that  we  have  dealt  with  today  were  not  necessarily  the  fault  of  the 
actual  hands-on  people  doing  the  audits.  Miss  McLaughlin,  for  ex- 
ample, was  a  career  employee  doing  audits.  In  my  opinion,  at  least 
from  what  I  can  tell — and  I  would  be  prepared  to  be  informed  oth- 
erwise if  I  am  wrong — basically  she  told  it  like  it  was  when  she  en- 
countered problems;  though  we  certainly  should  improve  the  audit 
process  and  the  scheduling  and  so  on. 

But  the  actual  hands-on  performance  of  the  audits  is  not  so 
much  of  the  problem  as  what  was  done  with  the  information,  once 
gathered.  I  believe  this  is  a  recurring  theme,  that  perhaps  most  of 
the  staff  that  worked  with  me  on  this  matter  would  agree,  that 
there  is  an  identification  of  a  problem,  it  is  sitting  there,  it  stays 
in  a  file,  and  there  appears  to  be  no  action  and  no  apparent  expla- 
nation for  the  inaction.  So  I  believe  that  it  is  a  matter  of  philoso- 
phy as  much  as  it  is  resources  and  the  commitment.  You  have  to 
want  to  act  on  your  information. 


210 

Mr.  SCHAEFER.  Right.  I  am  sure  you  heard  testimony  just  prior 
to  this  as  regards  these  audit  reports.  Too  many  times,  as  I  cer- 
tainly understand  it,  they  didn't  reach  the  point  where  they  should 
have.  So  all  of  this  information  sitting  out  there  as  to  all  of  these 
various  problems  that  we  have,  and  it  never  reached  the  proper 
people. 

Mr.  Broder.  Either  it  didn't  reach  the  proper  people  or  for  what- 
ever reason,  perhaps  well  justified  or  not,  appropriate  decision- 
making was  not  based  on  the  facts  as  they  were  available. 

Mr.  SCHAEFER.  Do  you  believe  that  they  are  understaffed  as  far 
as  the  administration  level  goes? 

Mr.  Broder.  I  do  not  believe  that  they  are  understaffed,  and  I 
am  not  sympathetic,  at  least  excessively  sympathetic  to  the  argu- 
ment that  most  of  the  problems  that  we  have  heard  today  are  fo- 
cused on  resources. 

Yes,  if  you  were  at  an  appropriations  hearing,  I  would  certainly 
give  you  a  very  good  defense  of  why  we  need  a  budget  and  why  we 
need  certainly  the  President's  budget.  But  I  don't  believe  that  most 
of  these  issues  that  we  have  encountered  today  are  focused  on  re- 
sources per  se,  and  I  actually  feel  that  is  taking  us  a  little  bit  away 
from  the  point. 

Mr.  SCHAEFER.  So  just  with  a  little  bit  of  streamlining  in  the 
present  system,  it  could  probably  do  the  job  without 

Mr.  Broder.  Well,  I  don't  want  to  say  that  resources  aren't  rel- 
evant; they  are  always  relevant,  as  we  can  certainly  discuss,  and 
I  will  also  get  into  the  issue  of  resource  allocation  should  you  wish 
me  to,  but  I  think  that  it  is  basically  a  philosophy,  which  also  has 
to  be  a  part  of  the  process. 

We  have  to,  without  fear  of  favor,  as  much  as  human  beings  can, 
accept  data  as  thev  come  in.  That  is  what  a  scientist  really  must 
do,  and  auditing  from  my  point  of  view  is  a  specialized  kind  of 
science.  You  have  to  take  the  facts  as  they  come  in,  not  as  you 
want  them.  It  is  very  dangerous  for  a  scientist  or  a  doctor  to  ignore 
facts,  and  I  think  that  in  this  situation,  the  recognition  of  the  facts 
as  they  came  in,  and  an  appropriate  decision-making  process  after 
those  facts  were  known  would  have  gone  a  long  way  to  obviate 
many  of  the  problems  that  we  have. 

Mr.  SCHAEFER.  Well,  at  our  April  hearing.  Dr.  Friedman  testified 
that  two  people  had  been  added,  assigned  to  the  monitoring  of  the 
reports  that  came  in  from  the  University  of  Pittsburgh,  and  he 
stated  he  thought  this  was  inadequate.  Is  that  your  opinion  or  can 
you  even  make  an  opinion? 

Mr.  Broder.  Are  you  asking  whether  we  at  NCI  should  be  allo- 
cating more  resources? 

Mr.  SCHAEFER.  No.  Well,  I  am  just  saying,  he  stated  that  two 
people  added  is  inadequate,  it  is  not  sufficient. 

Mr.  Broder.  I  agree  with  that,  but  in  agreeing  with  that  I  want 
to  acknowledge  that  many  of  the  problems  which  this  committee 
has  identified  and  that  we  have  discussed  or  that  NCI  itself  have 
identified  are  not  linked  to  a  resource  issue. 

Yes,  resources  are  necessary,  and  I  pride  myself  in  being  pretty 
good  in  making  a  case  for  more  resources,  but  I  don't  believe  that 
is  an  issue  before  us  today.  Many  of  the  issues  that  were  identified 
earlier  had  to  do  with  not  acting  on  information  as  it  came  in,  in- 


211 

formation  that  auditors  had  picked  up,  information  that  was  in  a 
file — memos  that  one  investigator  at  NSABP  would  write  to  an- 
other investigator  without  a  follow  up.  I  believe  that  there  were  a 
lot  of  decision-making  issues. 

We  heard  earlier  today  discussions  about  endometrial  cancer 
deaths.  I  don't  believe  resources  are  the  issue  that  we  were  talking 
about. 

Mr.  SCHAEFER.  OK.  You  also  probably  heard  me — I  referred,  and 
the  chairman  did  too,  to  this  embargo  thing  in  a  couple  of  cases 
which  prevented  NSABP  from  announcing  the  presence  of  fraud  in 
studies.  Do  you  know  under  what  authority  such  an  embargo  can 
be  initiated? 

Mr.  Broder.  I  would  answer  that  in  two  ways.  First,  the  embar- 
go is  a  request  of  a  sister  agency  of  the  Public  Health  Service  to 
not  interfere  with  an  ongoing  investigation,  and  I  understand  the 
responsibilities  that  OKI  has  in  this  matter,  but  I  believe  you  and 
others  on  the  committee  very  carefully  pointed  out  that  the  embar- 
go ended  approximately  in  April  of  1993,  and  well  prior  to  the  end- 
ing of  the  embargo,  NCI  and  ORI  staff  had  communicated  to  the 
NSABP  that  we  expected  an  analysis  published  that  would  exclude 
the  Poisson  data  and  provide  a  notice  to  the  reader. 

What  we  are  talking  about  is  an  ethics  issue,  not  a  statistical 
issue.  It  is  a  notification  to  the  reader;  it  is  a  disclosure  to  the 
reader  that  there  is  a  problem. 

We  had  received  assurances  that  the  process  was  working  and 
that  a  paper  was  being  prepared.  It  was  a  surprise  to  us  to  learn 
that  in  fact,  did  not  occur,  and,  please,  I  might  want  to  add  one 
other  thing. 

There  was  a  publication  that  came  out  in  June  of  1993  which  ex- 
cluded the  data  from  the  St.  Luc's  site.  There  was  a  galley  proof 
still  available  in  April  of  1993.  The  individual  patients  from  St. 
Luc's  Hospital  appear  to  have  been  removed  without  a  disclosure 
to  the  reader. 

So  those  are  just  the  facts  as  I  know  them,  and  I  have  had  dis- 
cussions with  the  editor  of  the  New  England  Journal  of  Medicine 
on  this  topic.  So  it  is  certainly  possible  to  argue,  as  you  have  suc- 
cessfully done,  that  there  were  substantial  delays  here,  and  we  are 
sorry  for  them. 

Mr.  ScHAEFER.  It  gets  back  to  the  people's  right  to  know,  as  we 
indicated. 

One  final  question,  Mr.  Chairman.  Was  NCI  responsible  for  al- 
tering the  consent  form  as  Dr.  Fisher  alleges? 

Mr.  Broder.  The  NCI  submitted  an  informed  consent  in  re- 
sponse to  a  request  by  the  Food  and  Drug  Administration  to  spe- 
cifically address  the  mortality  implications  of  endometrial  cancer, 
and  relied  on  Dr.  Fisher's  and  others'  presentation  of  information 
from  their  database.  They  were  asked  were  there  endometrial  can- 
cer deaths  and  we  were  told  no.  We  must  rely  on  the  grantee  in 
these  matters.  I  believe  it  was  a  joint  decision. 

Mr.  Schaefer.  So  was  it  only  because  Mr.  Fisher  had  not  re- 
ported the  deaths? 

Mr.  Broder.  Well,  as  you  heard  his  testimony  today,  he  agreed 
with  the  inclusion  of  the  statement,  and  from  his  point  of  view,  it 
was  valid  as  of  the  time  of  the  insertion.  Had  we  known  then  what 


212 

we  know  now,  that  statement  would  not  be  in  there,  and  I  submit 
to  you  that  the  grantee  has  a  duty  to  inform  us. 

One  of  the  things  that  I  noticed  in  the  testimony  up  until  now 
is  that  there  was  a  great  deal  of  discussion  about  reporting  to 
Zeneca,  the  pharmaceutical  company,  and  so  on  and  so  forth.  As 
they  said  in  Cool  Hand  Luke:  What  we  have  here  is  a  failure  to 
communicate.  And  basically  I  think  that  we  should  have  known 
that  there  were  deaths.  We  are  the  grantor,  and  if  there  are  dif- 
ficulties of  sorting  them  out,  then  we  will  be  happy  to  participate. 

I  don't  think  it  is  appropriate  for  us  to  learn  at  a  scientific  meet- 
ing as  the  company  has  expressed,  that  there  is  a  new  and  unre- 
ported side  effect.  That  puts  us  in  the  status  of  just  another  partici- 
pant in  the  study,  and  I  reject  that  concept.  We  are  the  grantor. 

Mr.  SCHAEFER.  So  you  didn't  know  what  Dr.  Fisher  knew. 

Mr.  Broder.  We  learned  at  the  public  presentation,  which  was 
at  the  end  of  October. 

Mr.  SCHAEFER.  Yes.  I  couldn't  agree  with  you  more  on  that  last 
one. 

Mr.  DiNGELL.  The  Chair  thanks  the  gentleman. 

Dr.  Broder,  the  Chair  would  like  to  thank  you  for  your  very  help- 
ful testimony  to  us  today.  We  always  are  appreciative  of  your  kind- 
ness and  the  very  fine  job  you  are  aoing  at  NCI. 

You  appeared  before  the  subcommittee  approximately  2  months 
ago  and  were  aware  of  the  problems  in  the  NSABP  trial  sites  at 
St.  Luc's  and  were  beginning  to  learn  about  the  problems  at  St. 
Mary's.  Based  on  your  testimony  today,  it  appears  that  NCI  has 
learned  a  lot  more  about  the  management  and  operations  at 
NSABP  and  its  sites  since  that  time. 

Can  you  characterize  for  the  subcommittee  what  you  found  re- 
garding the  management  and  operation  at  NSABP  and  its  sites, 
please? 

Mr.  Broder.  I  think  on  balance,  we  have  observed  that  we  must 
have  a  more  organized  and  objective  set  of  criteria  for  who  can  be 
a  participating  member;  we  must  have  more  effective  follow  up  and 
communication  with  the  participants;  we  must  have  a  process  in 
which  problems  are  identified  quickly,  and  basically,  if  possible, 
corrected  by  the  grantee,  not  simply  corrected  by  the  NCI  coming 
in  on  an  emergency  basis.  The  final  responsibility  for  these  issues 
must  lay  with  the  grantee. 

I  think  that  those  are  the  major  issues,  that  basically  we  must 
have  a  more  organized  and  effective  method  of  adhering  to  protocol 
eligibility  and  to  following  the  clinical  trials  as  they  are  designed. 
And  I  think  we  are  working  in  that  direction. 

I  think  Dr.  Herberman  has  expressed  an  extreme  commitment  to 
this  point,  and  I  am  rather  pleased  with  the  direction  that  he  has 
been  able  to  do  an  interim  principal  investigator. 

Mr.  DiNGELL.  Now,  Doctor,  we  have  heard  a  number  of  expla- 
nations as  to  why  the  problems  have  occurred.  For  example,  lack 
of  audit  resources,  and  it  does  appear  that  there  is  a  deficiency 
here;  lack  of  an  executive  director  to  handle  management  adminis- 
tration; that  the  trials  grew  too  quickly.  I  would  like  to  get  your 
thoughts  with  regard  to  the  matters  before  the  committee  today. 

First,  with  regard  to  the  issue  of  lack  of  audit  resources,  did  NCI 
underfund  audit  requests  made  by  Pittsburgh? 


213 

Mr.  Broder.  The  short  answer  is  no.  I  will  elaborate  if  the  Chair 
asks,  but  the  answer  is  no,  and  I  will  provide  you  with  the  informa- 
tion either  now  or  for  the  record. 

[The  following  information  was  received:] 


214 


f        ^^      DEPABTMENT  OF  HEALTH  &  HUMAN  SERVICES  Public  Health  Sorvice 


National  Institutes  of  Health 
_,__,_„     .    -^T  »^  TT  ••«•  National  Cancer  Institute 

MEMORANDUM  BethesOa,  Maryland  20892 


DATEi  June    14,     1994 

FROM:  Section    Chief,    GAB,    OAM,    NCI 

SUBJECT:  NSABP  Audit   Support 

TOi  Chief,    GAB,    OAM,     NCI 


The  following  represents  a  comparison  of  the  funds  requested, 
recommended  and  awarded  on  CA12027-20,  21,  22  and  23  and  CA37377- 
07,  08  and  09  for  NSABP  staff  on-site  audits  of  the  NSABP 
participant  institutions.   It  also  includes  a  comparison  of  the 
amounts  awarded  and  expended  for  CA12027-21,  22  and  23  and 
CA37377-09  for  audit  travel.   (To  date,  we  have  not  requested 
expenditures  for  years  07  and  08  on  CA37377.)   I  have  indicated 
the  FY  involved  and  the  budget  period. 

Attachment  1  compares  the  direct  cost  support  requested  by  NSABP 
for  the  audit  functions  to  the  amount  recommended  by  peer  review, 
the  amount  subsequently  requested  by  NSABP  in  response  to  NCI 
funding  plans  or  Type  5  committed  levels,  and  the  amount  awarded 
by  NCI  for  audit  functions  for  CA12027-20,  21,  22  and  23  and 
CA37377-07,  08  and  09. 

In  Attachment  2,  I  have  provided  a  comparison  of  the  funds 
awarded  for  audit  travel  to  the  reported  NSABP  expenditures  of 
travel  funds  for  years  21,  22  and  23  of  CA12027  and  year  09  of 
CA37377.   This  is  the  information  requested  of  Mr.  Crouch  in  our 
April  8  and  June  2  letters.   The  reason  for  reflecting  only  the 
travel  amounts  is  that  for  the  21  and  22  years  of  CA12027, 
figures  were  only  provided  for  the  expenditures  on  travel. 
However,  in  the  report  on  the  09  year  of  CA37377,  he  indicates 
budgeted  and  expended  funds  for  auditors.   In  our  review  of  the 
file,  we  can  not  find  reference  to  a  request  for  salaries 
specifically  for  auditors,  so  I  have  removed  those  amounts  from 
the  reported  expenditures  to  allow  comparability  of  cost  pools. 
(The  budgets  for  CA12027  included  salaries  and  other  costs  and, 
therefore,  those  figures  are  included  in  Attachment  1.) 

I  have  attached  copies  of  the  information  that  Michael  Crouch 
provided  in  response  to  our  requests  of  April  8  and  June  2,  1994, 
in  which  we  asked  for  a  description  of  the  audits  which  were 
planned  for  each  year  as  compared  to  the  audits  which  were 
actually  performed  and  the  associated  cost  of  each  audit. 

If  additional  information  is  required,  please  let  me  know. 


215 


ATTACHMEMT    1 
DIRECT    COST    80PPORT    FOR    ADDIT    FUMCTION    OF    NSABP 


PROJECT/YEAR 

CA12027-20 

FY  91 
(2/1/91-1/31/92) 

CA12027-21 

FY92 
(2/1/92-1/31/93) 

CA12027-22 

FY93 
(2/1/93-1/31/94) 

CA12027-23 
FY94 
(2/1/94-1/31/95) 


ORIO.  NSABP 
REQUESTED 
DIRECT  COST 

S  52,076 


181,923 


REVIEW 
RECOMM. 

LEVEL 


FINAL 
NSABP  REQ. 
BUDGET 


Unavail. 


115,280 


S  76,413 


84,295 


NCI 

AWARDED 
DIRECT  COST 

$  71,838 


84,295 


192,095 


202,851 


41,459 


CA37377-07* 

FY91 
(8/1/91-5/31/92  Ten  months) 


Unspecified   90,100 


Unspecified  185,960 


Unspecified   21,555 


CA37377-08* 

FY92 
(6/1/92-5/31/93) 

CA37377-09* 

FY93 
(6/1/93-8/31/94)** 
TOTAL 


Unspecified  Unspecified   49,759 


Unspecified  Unspecified   92,923 


$601,005 


84,466 


174,803 


21,555 


45,136 


90,750 


$572,843 


*   Requested  support  for  travel  only. 
**  09  year  extended  at  no-cost  for  3  months  from  5/31/94  to  8/31/94. 

Definition  of  Columns 

Column  1  -  Original  requested  levels  found  in  application.   If  no  detail  was 
provided  in  the  competing  application  for  specific  amounts  requested  for  audit 
support  in  future  years,  then  unspecified  is  indicated. 

Column  2  -  Correct  recommended  level  based  on  peer  review  summary  statement. 
If  no  detail  was  provided  for  audit  in  future  years  summary  statement 
description,  unspecified  is  indicated. 

Column  3  -  NSABP 's  final  budget  request  based  on  NCI  funding  availability  in 
competing  years  (CA12027-21  and  CA37377-07)  or  Type  5  commitment  level  shown 
on  award  notice. 


Column  4  -  NCI's  awarded  amount  based  on  funding  plan  level  for  each  year  and 
programmatic  review  of  request. 


216 


ATTACHMENT  2 
COMPARISON  OF  AUDIT  TRAVEL  FUKD8  AWARDED  TO  EXPENDED 


NCI 

NSABP 

AWARDED 

EXPENDED 

PROJECT /YEAR 

TRAVEL 

TRAVEL 

CA12027-21 

$  29,389 

$21,579. 

FY92 

(2/1/92  -  1/31/93) 

CA12027-22  26,713 

FY93 
(2/1/93  -  1/31/94) 

CA12027-23  86,851 

FY93 
(2/1/94  -  4/30/94) 

CA37377-09  83,393 

FY93 
(6/1/93  -  4/30/94) 


DIFFERENCE 


10,035.22       •  16,677.78 


3,683.44        83,167.56 


64,555.28        18,837.72 


TOTAL  TRAVEL 


$226,346        $99,853.55       $126,492.45 


217 

Mr.  DiNGELL.  Now,  then  there  is  the  next  question  of  did  the 
trials  grow  too  fast?  I  don't  believe  that  NCI  was  ever  told  that 
NSABP  officials  were  concerned  about  the  rate  of  recruitment  and 
worried  about  the  effect  that  this  would  have  on  the  quality  of  the 
work  being  done;  is  that  correct? 

Mr.  Broder.  Well,  it  is  very  difficult  for  me  to  understand  that 
the  trials  were  going  too  fast.  There  was  a  grant  put  in.  The  grant 
was  put  in  by  the  NSABP  to  perform  a  trial. 

Presumably,  the  grantee  knows  what  the  grantee  is  asking  in  the 
trial,  and  that  is  a  point  that  is  a  little  difficult  for  me  to  follow. 
The  trial  was  to  do  a  major  prevention  study,  and  it  had  expecta- 
tions and  growth. 

With  the  Chair's  indulgence,  I  cannot  resist  getting  back  to  the 
budget  issue.  I  apologize.  I  need  to  define  one  point. 

At  the  type  two  or  recompetition  phase  of  a  grant,  an  applicant 
will  come  in  with  a  request.  I  am  giving  you  numbers  that  are  ap- 
proximate, but  they  are  in  the  rough  ball  park.  For  example,  one 
of  NSABP's  grants  in  the  prior  year,  or  the  last  year  in  the  pre- 
vious cycle  might  have  been  $4.5  million,  approximately.  As  they 
came  in  for  the  renewal  or  recompetition,  they  may  request  from 
us  $9  million,  or  a  100  percent  increase.  The  peer  reviewers  may 
cut  that  to  $8.1  million,  and  since  we  do  not  have  infinite  growth 
potential  we  may  end  up  finally  giving  the  NSABP  on  that  grant 
$6.5  million.  Now,  $6.5  million  is  a  substantial  level  of  growth  com- 
pared to  $4.5  million,  but  it  is  certainly  a  cut  compared  to  $9  mil- 
lion. 

Mr.  DiNGELL.  It  is  about  a  50  percent  increase. 

Mr.  Broder.  Right.  So  it  depends  on  how  you  want  to  look  at  it. 

The  final  programming  of  resources  within  the  total  award  in  all 
of  these  matters  is  in  the  hands  of  the  grantee.  The  final  decision 
is  made  when  we  receive  a  final  NSABP  budget  request.  That  is 
what  the  grantee  is  telling  us  they  need,  and  that  was  the  point 
you  were  raising  earlier.  That  is  what  the  grantee  is  telling  us, 
that  they  want  to  do — that  is  their  best  determination — and  we  ne- 
gotiate. We  would  always  give  more  flexibility  if  the  grantee  asked, 
and  sometimes  there  is  money  left  over  for  procedural  reasons  at 
the  end  of  a  year  and  they  would  be  most  welcome  to  make  a 
rebudgeting  request. 

In  addition,  you  should  be  aware  that  at  the  front  end  of  the 
original  request  it  is  not  uncommon  for  the  auditing  function  to  be 
unspecified,  and  the  specification  of  the  amount  actually  doesn't 
come  in  until  the  final  budget  negotiations.  So  I  am  sorry  to  have 
taken  your  time  with  the  arcana  of  NIH  grants  management,  but 
I  certainly  do  not  accept  the  principle  that  we  at  NCI  inappropri- 
ately cut  a  deserving  audit  function.  I  think  there  was  certainly 
less  money  to  go  across  the  board  for  all  of  the  research  effort,  but 
the  exact  proportionality  that  one  chooses  to  commit  for  budgeting 
for  auditing  is  in  the  hands  of  the  grantee.  And,  finally,  as  I  say, 
many  of  the  issues  that  we  encountered  don't  have  anything  to  do 
with  resources. 

Mr.  DiNGELL.  Now,  there  the  two  other  things  that  we  have 
heard  in  the  questions  of  the  matter  before  us.  One  is  the  request 
of  need  for  some  kind  of  better  management,  for  example,  a  direc- 
tor type  position  that  could  handle  management  administration. 


218       3  9999  05982  385  4 

Did  the  people  at  NSABP  ever  indicate  that  they  would  need 
some  kind  of  assistance  of  this  sort  to  handle  the  trials  because 
they  lack  the  capability  to  administer  the  project  properly? 

Mr.  Broder.  No.  And  Dr.  Fisher  is  a  great  man  and  has  made 
great  contributions.  Anyone  who  knows  NSABP  will  know  that  Dr. 
Fisher  is  the  person  who  runs  NSABP. 

Mr.  DiNGELL.  I  got  sort  of  the  opinion  that  sometimes  maybe  it 
was  somebody  else  running  it;  I  was  not  altogether  clear  who  was 
running  it  at  this  point. 

Mr.  Broder.  That  is  the  basis  of  my  statement. 

Mr.  DiNGELL.  Now,  you  heard  Dr.  Detre  earlier  this  morning 
about  the  culture  deference  given  the  senior  scientists.  I  think  that 
deference  is  required,  but  I  am  curious,  is  the  deference  going  be- 
yond their  ability  to  address  the  problems  that  they  confront  in 
terms  of  actually  administrating  a  project  of  this  kind? 

Mr.  Broder.  I  think  you  are  raising  an  excellent  point.  Inherent 
in  your  question  is,  ate  the  attributes  that  require  creative  sci- 
entific thinking  the  very  same  attributes  that  are  necessary  for  an 
executive  of  clinical  trials  administration?  I  think  that  is  a  valid 
point  and  we  are  certainly  considering  it. 

I  think  we  may  need  to  look  at  and  pay  more  attention  to  the 
difference  between  the  scientific  and  creative  process,  the  genius 
which  Dr.  Fisher  has,  and  he  is  a  genius,  in  the  development  of 
certain  aspects  of  the  scientific  outline  of  a  study  compared  to  how 
one  executes  that  study  and  how  one  then  pays  attention  to  the  in- 
credibly important  details  that  are  necessary  to  make  the  thing 
work.  And  I  think  that  we  will  certainly  look  at  that  issue. 

Human  nature  is  difficult  to  change,  and  of  course  if  you  are  in 
charge  of  a  study,  sometimes  you  want  to  be  in  charge  of  every- 
thing, and  that  is  one  of  the  issues  we  will  have  to  grapple  with. 
But  we  are  certainly  looking  into  whether  we  should  be  more  effec- 
tive at  circumscribing  activities,  so  that  an  administrator  or  admin- 
istratively oriented  person  may  run  the  audits  and  possibly  be  in 
charge  of  certain  issues  related  to  quality  assurance,  and  that  need 
not  be  the  same  person  that  develops  new  scientific  ideas,  and 
often  wouldn't  be.  There  is  no  harm  or  shame  in  saying  that.  There 
is  specialization  in  all  fields. 

Mr.  DiNGELL.  Thank  you,  Doctor.  Now,  Doctor,  the  last  time  you 
were  here  we  discussed  the  four  endometrial  cancer  deaths  in  re- 
cent treatment  trials.  I  note  that  there  has  now  been  a  fifth  that 
has  been  brought  to  the  attention  of  NCI  through  notification.  Can 
you  tell  us  briefly  about  this  particular  death  and  the  cir- 
cumstances that  attend  it? 

Mr.  Broder.  We  were  made  aware  of  an  additional  death,  I  be- 
lieve that  came  to  our  attention  in  May  of  this  year,  that  appar- 
ently had  occurred  in  December  of  1993.  I  would  be  happy  to  pro- 
vide the  details  for  you  for  the  record.  I  don't  know  the  specifics 
of  how  the  case  was  diagnosed. 

Mr.  DiNGELL.  Well,  it  appears  that  the  NSABP  learned  of  it  in 
April,  as  a  matter  of  fact  April  8  of  1994,  and  they  informed  the 
NCI  of  it  the  first  week  in  June.  Is  that  right? 

Mr.  Broder.  I  thought  it  was  May,  but  it — I  have  staff  here  who 
could  answer  that  question. 

Mr.  DiNGELL.  You  would  know  better  than  I  would. 


219 

Mr.  Broder.  I  apologize.  It  was  June  3rd.  You  are  quite  correct. 
June  3rd. 

Mr.  DiNGELL.  Doctor,  it  is  always  a  privilege  to  have  you  here 
before  the  committee.  I  want  to  express  my  thanks  to  you,  my  com- 
mendations of  the  fine  job  you  are  doing. 

I  would  like  to  have  a  few  concluding  remarks.  First  to  you.  Dr. 
Broder,  congratulations,  and  both  for  your  testimony  and  for  your 
leadership  in  this  area.  We  think  that  it  is  important  that  you  con- 
tinue to  do  so,  because  it  is  not  the  business  of  this  committee  to 
try  and  be  the  policeman  of  science;  we  want  the  scientists  to  do 
that  themselves  rather  than  us. 

To  Doctors  O'Connor,  Herberman,  and  Detre,  I  want  to  commend 
you  for  your  testimony  today,  gentlemen.  I  know  it  was  not  an  easy 
day  for  you,  and  it  is  not  the  practice  of  this  committee  to  make 
our  days  easy  for  our  witnesses.  But  your  testimony  indicates  that 
you  have  a  solid  understanding  of  the  portions  that  contribute  to 
the  misfortunes  in  the  NSABP  matter,  as  well  as  remedial  actions 
that  need  to  be  taken  to  make  this  institution  a  responsible,  pro- 
ductive enterprise  once  again,  and  I  commend  you  for  that. 

We  will  observe  the  continued  developments  in  this  matter,  in 
particular  the  implementations  of  the  promised  reforms  with  great 
interest,  and  we  express  to  you  our  good  wishes  that  you  be  suc- 
cessful in  that,  because  it  is  important. 

You  come  from  a  great  institution,  one  of  which  you  are  justifi- 
ably proud,  and  I  know  you  want  to  make  it  better,  and  it  is  the 
good  wishes  of  this  committee  that  you  shall  be  successful  in  mak- 
ing it  better. 

We  hope  that  this  whole  matter  will  now  be  brought  to  a  happy 
conclusion,  because  we  know  the  importance  of  the  work  that  is 
being  done  here,  and  to  the  surprise  of  some  in  the  scientific  com- 
munity, this  committee,  this  subcommittee,  and  this  particular 
chairman  have  spent  a  great  deal  of  time  and  effort  and  money  to 
see  to  it  that  NIH  is  a  success,  it  is  adequately  funded,  that  you 
scientists  and  educators  and  research  specialists  of  different  kinds 
are  successful  in  your  understanding  because  they  are  very  impor- 
tant to  us  and  to  the  country. 

So  we  express  our  thanks  to  all  who  assisted  us  today.  We  com- 
mend our  witnesses;  we  give  them  our  good  wishes  for  continued 
success,  and  we  call  the  committee  to  an  adjournment. 

[Whereupon,  at  4:03  p.m.,  the  hearing  was  adjourned.] 

o 


84-510    (224) 


ISBN  0-16-046276-2 


9  780 


60"462764 


90000